6-substituted thia-aza compounds

ABSTRACT

The invention relates to azetidin-2-ones of the formula ##STR1## wherein R a  represents hydroxy-lower alkyl, R 1  represents hydrogen, an organic radical bonded by a carbon atom to the ring carbon atom or an etherified mercapto group, R 2   A  together with the carbonyl group to which it is attached is a protected carboxyl group and Z&#39; is oxygen, sulfhur or an optionally substituted methylidene group, functional groups in the radicals R a , R 1  and Z&#39; optionally being in protected form. The azetidinones are useful intermediates for the preparation of penem antibiotics.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application of application Ser. No.152,526 filed Feb. 5, 1988, now abandoned; which is a divisionalapplication of application Ser. No. 057,082, filed June 3, 1987, nowabandoned, which is a divisional application of application Ser. No.208,105 filed Nov. 18, 1980 now U.S. Pat. No 4,692,442, which is acontinuation application of application Ser. No. 007,453 filed Jan. 29,1979, now abandoned.

The present invention relates to new bicyclic thia-aza compoundscontaining a β-lactam ring substituted in the 3-position and havingantibiotic properties.

Since the discovery of penicillin, numerous bicyclic thia-aza compoundshaving a β-lactam structure have become known. A survey of earlier worksis made by E. H. Flynn, "Cephalosporins and Penicillins", AcademicPress, New York and London, 1972. More recent developments are describedby J. Cs. Jaszberenyi et al., Progr. Med. Chem., Vol. 12, 1975, 395-477,and a P. G. Sammes, Chem. Rev. 1976, Vol. 76, No. 1, 113-155 and byvarious authors at an international symposium of the Chemical Societyheld in Cambridge, England in June, 1976, (subsequent publication: J.Elks, "Recent Advances in the Chemistry of β-lactam Antibiotics", TheChemical Society, Burlington House, London, 1977).

Apart from the usual penam and cephem compounds carrying an acylaminogroup in the 6- or 7-position, such compounds that are unsubstituted inthese positions have also become known, for example3-carboxy-2,2-dimethylpenam (J. P. Clayton, J. Chem. Soc., 1969, 2123)and 3-methyl-4-carboxy-3-cephem (K. Kuhlein, Liebigs Ann., 1974, page369 and D. Bormann, ibid., page 1391). 3-carboxy-2,2-dimethylpenamcompounds, that instead of the customary 6β-acylamino group have a6α-chloro or 6α-bromo group, have been described by I. McMillan and R.J. Stoodley, Tetrahedron Lett. 1205 (1966), and J. Chem. Soc. C 2533(1968), whilst corresponding 6α-hydroxy-, 6α-acetoxy- and6α-phenoxyacetoxy-2,2-dimethylpenam-3-carboxylic acids have beendescribed by D. Hauser and H. P. Sigg, Helv. Chimica Acta 50, 1327(1967). None of these compounds, however, has any, or any substantial,antibiotic activity.

6-acylamino-2-penem-3-carboxylic acid compounds having an antibioticactivity that contain the novel 2-penem ring system are described in DOSNo. 2 655 298.

2-penem compounds carrying in the 6-position substituents other thanacylamino are not so far known.

The problem underlying the present invention is to produce bicyclicthia-aza compounds containing a β-lactam ring that possess the 2-penemring system substituted in the 6-position and that are active againstboth penicillin-sensitive and penicillin-resistant bacteria.

The manufacture according to the invention of the novel compounds andthe new intermediates required therefor open up new fields in whichresearch into other commercially valuable compounds can be carried out.

The ring system of the compounds of the present invention has theformula ##STR2## and may systematically be called7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene. For the sake of simplicityit is referred to hereinafter as "2-penem", wherein the followingnumbering derived from penam and customary in penicillin chemistry shallbe used: ##STR3##

The present invention relates to 2-penem-3-carboxylic acid compounds ofthe formula ##STR4## in which R_(a) represents an organic radical bondedby a carbon atom to the ring carbon atom, a free, etherified oresterified hydroxy or mercapto group or a halogen atom,

R₁ represents hydrogen, an organic radical bonded by a carbon atom tothe ring carbon atom, or an etherified mercapto group, and

R₂ represents a hydroxy group or an radical that together with thecarbonyl grouping --C(═O)-- forms a protected carboxyl group,

and to salts of such compounds with salt-forming groups, processes forthe manufacture of such compounds, pharmaceutical preparationscontaining compounds of the formula I with pharmacological properties,and the use of the new compounds either as pharmacologically activesubstances, preferably in the form of pharmaceutical preparations, or asintermediates.

An organic radical R_(a) bonded by a carbon atom to the ring carbon atomis especially a saturated or unsaturated, optionally substituted,aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic oraliphatic hydrocarbon radical having up to 18, preferably up to 10,carbon atoms, or an optionally substituted heterocycl orheterocyclyl-lower alkyl radical having up to 10 carbon atoms and up to4 ring hetero atoms selected from the group nitrogen, oxygen and/orsulphur, especially optionally substituted lower alkyl or lower alkenyl,optionally functionally modified carboxyl, or optionally substitutedcycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkyl-loweralkenyl, cycloalkenyl-lower alkyl, phenyl, phenyl-lower alkyl orphenyl-lower alkenyl. Examples of substituents of such radicals areoptionally functionally modified, such as optionally etherified oresterified hydroxy or mercapto groups, for example hydroxy, loweralkoxy, for example methoxy or ethoxy, lower alkanoyloxy, for exampleacetoxy or propionoxy, hydroxysulphonyloxy present in said form, halogenatoms, for example chlorine or bromine, or lower alkylthio groups, forexample methylthio; optionally functionally modified carboxyl groups,such as carboxyl, lower alkoxycarbonyl, for example :methoxycarbonyl orethoxycarbonyl groups, carbamoyl or cyano; also nitro; sulpho present insalt form, or optionally substituted amino, such as aminomono-substituted or di-substituted by lower alkyl, for example methyl orethyl or by acyl, such as lower alkanoyl, for example acetyl, or aminodi-substituted by lower alkylene, for example 1,4-butylene or1,5-pentylene.

A lower alkyl radical R_(a) contains up to 7, especially up to 4, carbonatoms, and is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert.-butyl or pentyl. Substituted lower alkyl R_(a) isespecially substituted methyl, ethyl or propyl, the substituentsstanding especially in the 1-, but also in the 2- or 3-position, and is,for example, hydroxy-lower alkyl, such as hydroxymethyl, hydroxyethyl orhydroxypropyl; lower alkoxy-lower alkyl, such as lower alkoxymethyl,lower alkoxyethyl or lower alkoxypropyl, for example methoxymethyl,methoxyethyl or methoxypropyl; lower alkanoyloxy-lower alkyl, such aslower alkanoyloxymethyl, lower alkanoyloxyethyl or loweralkanoyloxypropyl, for example acetoxymethyl, propionoxymethyl,acetoxyethyl, acetoxypropyl, in salt form, for example in the form of analkali metal salt, such as a sodium salt; or hydroxysulphonyloxy-loweralkyl, such as hydroxysulphonyloxymethyl, hydroxysulphonyloxyethyl orhydroxysulphonyloxypropyl, present in the form of an ammonium salt;halo-lower alkyl, such as halomethyl, haloethyl or halopropyl, forexample chloroethyl or bromoethyl or chloropropyl or bromopropyl; loweralkylthio-lower alkyl, such as methylthiomethyl, methylthioethyl,methylthiopropyl or tert.-butylthiomethyl; lower alkoxycarbonyl-loweralkyl, such as lower alkoxycarbonylmethyl or lower alkoxycarbonylethyl,for example, methoxycarbonylmethyl, methoxycarbonylethyl,ethoxycarbonylmethyl or ethoxycarbonylethyl; cyano-lower alkyl, such ascyanomethyl or cyanoethyl; sulpho-lower alkyl, such as sulphomethyl,sulphoethyl or sulphopropyl, in which the sulpho group is present insalt form, for example in the form of an alkali metal salt, such as asodium salt, or in the form of an ammonium salt; or optionallyprotected, for example acetylated, amino-lower alkyl, such asaminomethyl, aminoethyl or aminopropyl.

A lower alkenyl radical R_(a) contains 2 to 7, especially 2 to 4 carbonatoms, and is, for example, vinyl, allyl or but-2-enyl or but-3-enyl.Substituted lower alkenyl may carry the same substituents as substitutedlower alkyl.

An optionally functionally modified carboxyl group R_(a) is a freecarboxyl group or one of the, for example esterified or amidated,carboxyl groups mentioned under the --C(═O)--R₂ ^(A) groups, such aslower alkoxycarbonyl, for example methoxycarbonyl, ethoxy henoxycarbonyloptionally substituted, for example, by halogen, such as chlorine, bylower alkoxy. such as methoxy, or by nitro, such as phenoxycarbonyl, o-,m- or p-chlorophenoxycarbonyl, pentachlorophenoxycarbonyl, o-, m- orp-methoxyphenoxycarbonyl or p-nitrophenoxycarbonyl; aminocarbonyl; orsubstituted aminocarbonyl, such as aminocarbonyl mono-substituted ordi-substituted by a lower alkyl group, for example methyl or ethyl.

A cycloalkyl radical R_(a) has, for example, 3 to 7 carbon atoms and is,for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, whereasa cyloalkyl-lower alkyl radical R_(a) contains, for example, 4 to 7carbon atoms and is, for example, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl or cyclohexylmethyl.

A cycloalkenyl radical R_(a) is a corresponding cycloalkyl radicalhaving one or optionally two C--C double bonds, such as cyclohexenyl,for example cyclohexenyl, or cyclohexadienyl, for examplecyclohexa-1,4-dienyl

A cycloalkyl-lower alkenyl radical or cycloalkenyl-lower alkyl radicalR_(a) is, for example, cyclohexylvinyl, cyclohexylallyl, orcyclohexenylmethyl or cyclohexa-1,4-dienylmethyl.

A phenyl or a phenyl-lower alkyl radical, for example a benzyl or 1- or2-phenylethyl radical R_(a) may be substituted, preferably in thearomatic radical, for example by lower alkyl, such as methyl or ethyl,by lower alkoxy, such as methoxy, or by halogen, such as fluorine orchlorine, further by nitro or by amino, wherein phenyl-lower alkyl maybe substituted in the position, for example, by hydroxy,hydroxysulphonyloxy, carboxy, sulpho or amino

In a heterocyclyl or heterocyclyl-lower alkyl radical R_(a), aheterocyclyl radical is a radical that is preferably of aromatic natureand is bonded by a carbon atom, such as pyridyl, for example pyridyl,pyrid-3-yl or pyrid-4-yl, thienyl, for example thien-2-yl, or furyl, forexample fur-2-yl, or a corresponding pyridyl-, thienyl- or furyl-loweralkyl, especially -methyl radical, wherein heterocyclyl-lower alkyl maybe substituted in the α-position, for example, by hydroxy,hydroxysulphonyloxy, carboxy, sulpho or amino.

A phenyl- or heterocyclyl-lower alkenyl radical R_(a) is a lower alkenylradical, for example phenylvinyl or furylallyl, substituted in the samemanner as a corresponding lower alkyl radical

A phenyl-, naphthyl- or heterocyclyl-lower alkenyl radical R_(a) is alower alkenyl radical, for example phenylvinyl or furylallyl,substituted in the same manner as a corresponding lower alkyl radical.

An etherified hydroxy group R_(a) is etherified by an optionallysubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic hydrocarbon radical having up to 18, especiallyup to 10 carbon atoms, and is especially optionally substituted loweralkoxy, cycloalkoxy, cycloalkyllower alkoxy, phenoxy, naththyloxy orphenyl-lower alkoxy. Examples of substituents of such radicals areoptionally functionally modified, such as optionally etherified oresterified, hydroxy or mercapto groups, for example hydroxy, loweralkoxy, for example methoxy or ethoxy, lower alkanoyloxy, for exampleacetoxy or propionoxy, halogen, for example chlorine or bromine, orlower alkylthio, for example methylthio; or optionally functionallymodified carboxyl groups, such as carboxyl, lower alkoxycarbonyl, forexample methoxycarbonyl or ethoxycarbonyl, carbamoyl or cyano; alsonitro; or optionally substituted amino, such as amino mono-substitutedor di-substituted by lower alkyl, for example methyl or ethyl, or byacyl, such as lower alkanoyl, for example acetyl, or aminodi-substituted by lower alkylene, for example 1,4-butylene or1,5-pentylene.

A lower alkoxy radical R contains up to 7, especially up to 4, carbonatoms, and is, inter alia, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tert.-butoxy or pentoxy. Substituted lower alkoxy R isespecially substituted methoxy, ethoxy or propoxy, the substituentsstanding in the 1-, 2- or 3-position, such as methoxymethoxy,ethoxymethoxy, methoxyethoxy or methoxypropoxy; loweralkanoyloxymethoxy, lower alkanoyloxyethoxy or lower alkanoyloxypropoxy,such as acetoxymethoxy, acetoxyethoxy or acetoxypropoxy; halomethoxy;haloethoxy or halopropoxy, such as chloroethoxy or bromoethoxy orchloropropoxy or bromopopoxy; lower alkoxycarbonylmethoxy or lower ralkoxycarbonylethoxy, for example methoxycarbonylmethoxy,ethoxycarbonylmethoxy or methoxycrbonylethoxy; cyanomethoxy,cyanoethoxy, or optionally protected aminomethoxy, aminoethoxy oraminopropoxy.

A cycloalkoxy group R_(a) has, for example, 3 to 7 carbon atoms and is,for example, cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexyloxy.

A cycloalkyl-lower alkoxy radical R_(a) has, for example, 4 to 7 carbonatoms and is, for example, cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy or cyclohexylmethoxy.

A phenoxy or phenyl-lower alkoxy radical R_(a), for example a benzyl- or1- or 2-phenylethoxy radical may be substituted, preferably in thearomatic radical, for example by lower alkyl, such as methyl or ethyl,by lower alkoxy, such as methoxy, by halogen, such as fluorine orchlorine, or by nitro or amino.

An esterified hydroxy group R_(a) is a hydroxy group esterified by anacyl radical of an optionally substituted aliphatic, cycloaliphatic,cycloaliphaticaliphatic, aromatic or araliphatic carboxylic acid havingup to 18 carbon atoms. Such groups are especially optionally substitutedlower alkanoyloxy, cycloalkanoyloxy, cycloalkyl-lower alkanoyloxy,benzoyloxy, or phenyl-lower alkanoyloxy. Substituents of such radicalsare, for example, optionally functionally modified, such as optionallyetherified or esterified, hydroxy or mercapto groups, for examplehydroxy, lower alkoxy, for example methoxy or ethoxy, aryloxy, forexample phenoxy, lower alkanoyloxy, for example acetoxy or propionoxy,halogen, for example chlorine or bromine, or lower alkylthio, forexample methylthio: or optionally functionally modified carboxyl groups,such as carboxyl, lower alkoxycarbonyl, for example methoxycarbonyl orethoxycarbonyl, carbamoyl or cyano; also nitro; or optionallysubstituted amino, for example amino mono-substituted or di-substitutedby lower alkyl, for example methyl or ethyl, or by acyl, such as loweralkanoyl, for example acetyl, or amino disubstituted by lower alkylene,for example 1,4-butylene or 1,5-pentylene.

A lower alkanoyloxy radical R_(a) contains up to 7, especially up to 4,carbon atoms, and is, for example, formyloxy, acetoxy, propionoxy orbutyryloxy. Substituted lower alkanoyloxy R_(a) is especially substituted acetoxy, for example, hydroxyacetoxy, methoxyacetoxy,phenoxyacetoxy, haloacetoxy, for example chloroacetoxy or bromoacetoxy,cyanoacetoxy or optionally protected glycyloxy.

A cycloalkanoyloxy radical R_(a) has 4 to 8 carbon atoms and is, forexample, cyclopropylcarbonyloxy, cyclobutylcarbonyloxy,cyclopentylcarbonyloxy or cyclohexylcarbonyloxy, or a correspondingradical substituted, for example, in the 1-position, for example byhydroxy or amino.

A cycloalkyl-lower alkanoyloxy radical R_(a) has 5 to 9 carbon atoms andis, for example, cyclopropylacetoxy, cyclobutylacetoxy,cyclohexylacetoxy or cyclohexylpropionoxy, or a corresponding radicalsubstituted, for example, in the 1-position, for example by hydroxy oramino.

A benzoyloxy or phenyl-lower alkanoyloxy radical R_(a), for example aphenylacetoxy radical, may be substituted, preferably in the aromaticradical, for example, by lower alkyl, such as methyl or ethyl, by loweralkoxy, such as methoxy, by halogen, such as fluorine or chlorine, bynitro or by optionally protected hydroxy or amino. In the phenyl-loweralkanoyloxy radical, optionally substituted, for example protected,hydroxy or optionally substituted, for example protected, amino, mayalso stand in the aliphatic moiety, especially in the 2-position.

An etherified mercapto group R_(a) is etherified by an optionallysubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic hydrocarbon radical having up to 18, especiallyup to 10 carbon atoms, and is especially optionally substituted loweralkylthio, cycloalkylthio, cycloalkyl-lower alkylthio, phenylthio orphenyl-lower alkylthio. Examples of substituents of such radicals areoptionally functionally modified, such as optionally etherified oresterified, hydroxy or mercapto, for example, hydroxy, lower alkoxy, forexample methoxy or ethoxy, lower alkanoyloxy, for example acetoxy orpropionoxy, halogen, for example chlorine or bromine, lower alkylthio,for example methylthio; or optionally functionally modified carboxylgroups, such as carboxyl, lower alkoxycarbonyl, for examplemethoxycarbonyl or ethoxycarbonyl, carbamoyl or cyano; also nitro; oroptionally substituted amino, such as amino mono-substituted ordi-substituted by lower alkyl, for example methyl or ethyl, or by acyl,such as lower alkanoyl, for example acetyl, or amino di-substituted bylower alkylene, for example by 1,4-butylene or 1,5-pentylene.

A lower alkylthio radical R_(a) contains up to a especially up to 4,carbon atoms, and is, inter alia methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, tert.-butylthio or pentylthio.Substituted lower alkylthio R_(a) is especially substituted methylthio,ethylthio or propylthio, the substituents standing in the 1-, 2- or3-position, such as methoxymethylthio, ethoxymethylthio,methoxyethylthio or methoxypropylthio; lower alkanoyloxymethylthio,lower alkanoyloxyethylthio or lower alkanoyloxypropylthio, such asacetoxymethylthio, acetoxyethylthio or acetoxypropylthio;halomethylthio, haloethylthio or halopropylthio, for examplechloroethylthio or bromoethylthio, or chloropropylthio orbromopropylthio; lower alkoxycarbonylmethylthio or loweralkoxycarbonylethylthio, for example methoxycarbonylethylthio;cyanomethylthio; cyanoethylthio; or optionally protected, for exampleN-acylated, aminomethylthio, aminoethylthio or aminopropylthio.

A cycloalkylthio group R_(a) has, for example, 3 to 7 carbon atoms andis, for example, cyclopropylthio, cyclobutylthio, cyclopentylthio orcyclohexylthio.

A cycloalkyl-lower alkylthio radical R_(a) has, for example, 4 to 7carbon atoms and is, for example, cyclopropylmethylthio,cyclobutylmethylthio, cyclopentylmethylthio or cyclohexylmethylthio.

A phenylthio or phenyl-lower alkylthio radical R_(a), for example abenzylthio or 1- or 2-phenyl-lower alkylthio radical, for example abenzylthio or 1- or 2-phenylethylthio radical, may be substituted,preferably in the aromatic radical, for example may lower alkyl, such asmethyl or ethyl, by lower alkoxy, such as methoxy, by halogen, such asfluorine or chlorine, by nitro or by amino.

An esterified mercapto group R_(a) is a mercapto group esterified by anacyl radical of an optionally substituted aliphatic, cycloaliphatic,cycloaliphaticaliphatic, aromatic or araliphatic carboxylic acid havingup to 18 carbon atoms. Such radicals are especially optionallysubstituted lower alkanoylthio, cycloalkanoylthio, cycloalkyl-loweralkanoylthio, benzoylthio or phenyl-lower alkanoylthio. Substituents ofsuch radicals are, for example, optionally functionally modified, suchas optionally etherified or esterified, hydroxy or mercapto groups, forexample hydroxy, lower alkoxy, for example methoxy or ethoxy, aryloxy,for example phenoxy, lower alkanoyloxy, for example acetoxy orpropionoxy, halogen, for example chlorine or bromine, or loweralkylthio, for example methylthio; or optionally functionally modifiedcarboxyl groups, such as carboxyl, lower alkoxycarbonyl, for examplemethoxycarbonyl or ethoxycarbonyl, carbamoyl or cyano; also nitro; oroptionally substituted amino, such as amino mono-substituted ordi-substituted for example by lower alkyl, for example methyl or ethyl,by acyl, such as lower alkanoyl, for example acetyl, or aminodi-substituted by lower alkylene, for example 1,4-butylene or1,5-pentylene.

A lower alkanoylthio radical R_(a) contains up to 7, especially up to 4,carbon atoms and is, for example, formylthio, acetylthio, propionylthioor butyrylthio. Substituted lower alkanoylthio R_(a) or R_(a) isespecially substituted acetylthio, for example hydroxyacetylthio,methoxyacetylthio or phenoxyacetylthio; haloacetylthio, for examplechloroacetylthio or bromoacetylthio; cyanoacetylthio or optionallyprotected glycylthio.

A cycloalkanoylthio radical R_(a) has 4 to 8 carbon atoms and is, forexample, cyclopropylcarbonylthio, cyclobutylcarbonylthio,cyclopentylcarbonylthio or cyclohexylcarbonylthio, or a correspondingradical substituted, for example, in the 2-position, for example byhydroxy or amino.

A cycloalkyl-lower alkanoylthio radical R_(a) has 5 to 9 carbon atomsand is, for example, cyclopropylacetylthio, cyclobutylacetylthio,cyclohexylacetylthio or cyclohexylpropionylthio, or a correspondingradical substituted, for example, in the 2-position, for example byhydroxy or amino.

A benzoylthio or phenyl-lower alkanoylthio radical R_(a), for example aphenylacetylthio radical, may be substituted, preferably in the aromaticradical, for example by lower alkyl such as methyl or ethyl, by loweralkoxy, such as methoxy, by halogen, such as fluorine or chlorine, bynitro or by optionally protected hydroxy or amino. In the phenyl-loweralkanoylthio radical, optionally substituted, for example protectedhydroxy or optionally substituted for example protected amino may alsostand in the aliphatic moiety, especially in the 2-position.

R_(a) in the meaning of a halogen atom is iodine or especially fluorine,chlorine or bromine.

An organic radical R₁ bonded by a carbon atom to the ring carbon atom isespecially a saturated or unsaturated, optionally substituted aliphatic,cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatichydrocarbon radical having up to 18, preferably up to 10, carbon atoms,or an optionally substituted heterocyclyl or heterocyclyl-lower alkylradical having up to 10 carbon atoms and up to 4 ring hetero atomsselected from the group nitrogen, oxygen and/or sulphur, especiallyoptionally substituted lower alkyl or lower alkenyl, optionallyfunctionally modified carboxyl, or optionally substituted cycloalkyl,cycloalkenyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl,cycloalkenyl-lower alkyl, phenyl, phenyl-lower alkyl or phenyl-loweralkenyl. Examples of substituents such radicals are optionallyfunctionally modified, such as optionally etherified or esterified,hydroxy or mercapto groups, for example hydroxy, lower alkoxy, forexample methoxy or ethoxy, or lower alkanoyloxy, for example acetoxy orpropionoxy groups, halogen atoms, for example chlorine or bromine, orlower alkylthio groups, for example methylthio, or a heterocyclylthioradical; this heterocyclyl radical is optionally substituted, hasaromatic properties or is partially saturated; substituents are, interalia, lower alkyl, especially methyl; hydroxylower alkyl, for examplehydroxymethyl; carboxy-lower alkyl, for example carboxymethyl or 1- or2-carboxyethyl; optionally N-substituted amino-lower alkyl, such asdi-lower alkylamino-lower alkyl, for example dimethylaminoethyl;sulpho-lower alkyl present in salt form, for example sulphomethyl or 1-or 2-sulphoethyl present in the form of a sodium salt; cycloalkyl, forexample cyclopentyl or cyclohexyl; aryl, such as phenyl optionallysubstituted by halogen, for example chlorine, or by nitro; aryl-loweralkyl, for example benzyl; or functional group, such as halogen, forexample fluorine, chlorine or bromine; optionally substituted amino,such as amino optionally mono-substituted or di-substituted by loweralkyl, for example amino, methylamino or dimethylamino; nitro; hydroxy;lower alkoxy, for example methoxy or ethoxy; or optionally functionallymodified carboxyl, such as carboxyl, esterified carboxyl, such as loweralkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl,optionally substituted, such as N-mono-lower alkylated or N,N-di-loweralkylated carbamoyl, for example N-methylcarbamoyl, orN,N-dimethylcarbamoyl, or cyano; as well as oxo or oxido; wherein one ormore such substituents are present and these are bonded especially toring carbon atoms, but alternatively, especially lower alkyl and oxido,are bonded to ring carbon atoms; such heterocyclic radicals areespecially monocyclic, five-membered, diaza-, triaza-, tetraza-,thiaza-, tiadiaza, thiatriaza-, oxaza- or oxadiazacyclic radicals ofaromatic nature optionally containing the above-mentioned substitutents,or corresponding radicals that are optionally substituted, for exampleby the above-mentioned substituents, having a fused benzene ring, suchas benzodiaza- or benzooxaza-cyclic radicals; monocyclic, six-memberedmonoazacyclic or diazacyclic radicals of aromatic nature optionallycontaining the above-mentioned substituents, especially oxido; orcorresponding partially saturated radicals optionally substituted, forexample by the above-mentioned substituents, especially oxo; orbicyclic, triazacyclic or tetrazacyclic radicals of aromatic natureoptionally substituted, for example by the above-mentionedsubstitutents; or corresponding partially saturated radicals optionallysubstituted, for example by the above-mentioned substitutents,especially oxo. Examples of such heterocyclyl radicals are imidazolyl,for example imidazol-2-yl; triazolyl optionally substituted by loweralkyl and/or phenyl, for example 1,2,3-triazol-4-yl,1-methyl-1H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl,5-methyl-1H-1,2,4-triazol-3-yl, 3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl,4,5-dimethyl-4H-1,2,4-triazol-3-yl or 4-phenyl-4H-1,2,4-triazol-3-yl;tetrazolyl optionally substituted by lower alkyl, -phenyl orhalo-phenyl, for example 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,1-phenyl-1H-tetrazol-5-yl, 1-(4-chlorophenyl)-1H-tetrazol-5-yl,1-carboxymethyl-1H-tetrazol-5-yl,1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl or 1-sodiumsulphomethyl-1H-tetrazol-5-yl; thiazolyl or isothiazolyl optionallysubstituted by lower alkyl or thienyl, for example thiazol-2-yl,4-(thien-2-yl)-thiazol-2-yl, 4,5-dimethylthiazol-2-yl, isothiazol-3-yl,isothiazol-4-yl or isothiazol-5-yl; thiadiazolyl optionally substitutedby lower alkyl, for example 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-methyl-1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl or1,2,5-thiadiazol-3-yl; thiatriazolyl, for example1,2,3,4-thiatriazol-5-yl; oxazolyl or isoxazolyl optionally substitutedby lower alkyl or phenyl, for example oxazol-5-yl, 4-methyloxazol-5-yl,oxazol-2-yl, 4,5-diphenyloxazol-2-yl or 3-methylisoxazol-5-yloxadiazolyl optionally substituted by lower alkyl, -phenyl, nitro-phenylor thienyl, for example 1,2,4-oxadiazol-5-yl,2-methyl-1,3,4-oxadiazol-5-yl, 2-phenyl-1,3,4-oxadiazol-5-yl,5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl or2-(thienyl)-1,3,4-oxadiazol-5-yl; benzimidazolyl optionally substitutedby halogen, for example benzimidazol-2-yl or 5-chlorobenzimidazol-2-yl;or benzoxazolyl optionally substituted by halogen or nitro, for examplebenzoxazol-2-yl, 5-nitrobenzoxazol-2-yl or 5-chlorobenzoxazol-2-yl;1-oxidopyridyl, for example 1-oxidopyrid-2-yl or4-chloro-1-oxidopyrid-2-yl; pyridazinyl optionally substituted byhydroxy, for example 3-hydroxypyridazin-6-yl; N-oxidopyridazinyloptionally substituted by lower alkyl, lower alkoxy or halogen, forexample 2-oxido pyridazin-6-yl, 3-chloro-1-oxidopyridazin-6-yl,3-methyl-2-oxidopyridazin-6-yl, 3-methoxy-1-oxidopyridazin-6-yl,3-ethoxy-1-oxidopyridazin-6-yl, 3-n-butoxy-1-oxidopyridazin-6-yl or3-(2-ethylhexyloxy)-1-oxidopyridazin-6-yl; or2-oxo-1,2-dihydropyrimidinyl, optionally substituted by lower alkyl,amino, di-lower alkylamino or carboxy, for example2-oxo-1,2-dihydropyrimidin-4-yl,6-methyl-2-oxo-1,2-dihydropyrimidin-4-yl,5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl,6-amino-2-oxo-1,2-dihydropyrimidin-4-yl,6-dimethylamino-2-oxo-1,2-dihyiropyrimidin-4-yl,5-carboxy-2-oxo-1,2-dihydropyrimidin-4-yl or6-carboxy-2-oxo-1,2-dihydropyrimidin-4-yl; triazolopyridyl, for examples-triazolo[4,3-a]pyrid-3-yl or 3H-v-triazolo[4,5-b]pyrid-5-yl; orpurinyl optionally substituted by halogen and/or lower alkyl, forexample purin-2-yl, purin-6-yl or 8-chloro-2-methylpurin-6-yl; also2-oxo-1,2-dihydropurinyl, for example 2-oxo-1,2-dihydropurin-6 -yl]; oroptionally functionally modified carboxyl groups, such as carboxyl,lower alkoxy carbonyl, for example methoxycarbonyl or ethoxycarbonyl,carbamoyl or cyano; also nitro; or optionally substituted amino, forexample amino mono-substituted or di-substituted by lower alkyl, forexample methyl or ethyl, by acyl, such as lower alkanoyl, for exampleacetyl, or amino di-substituted by lower alkylene, for example1,4-butylene or 1,5-pentylene.

A lower alkyl radical R₁ contains up to 7, especially up to 4, carbonatoms, and is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert.-butyl or pentyl. Substituted lower alkyl is especiallysubstituted methyl, ethyl or propyl, the substituents standingespecially in the 1-, but also in the 2- or 3-position, such ashydroxymethyl, hydroxyethyl or hydroxypropyl; lower alkoxymethyl, loweralkoxyethyl or lower alkoxypropyl, for example methoxmethyl,methoxyethyl or methoxypropyl; lower alkanoyloxymethyl, loweralkanoyloxyethyl or lower alkanoyloxypropyl, for example, acetoxymethyl,propionoxymethyl, acetoxyethyl or acetoxypropyl; halomethyl, haloethylor halopropyl, for example chloroethyl or bromoethyl, or chloropropyl orbromopropyl; methylthiomethyl, methylthioethyl, methylthiopropyl,tert.-butylthiomethyl, 1,2,3-triazol-4-ylthiomethyl,1H-tetrazol-5-ylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl,1-carboxymethyl-1H-tetrazol-5-ylthiomethyl,1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl or 1-sodiumsulphomethyl-1H-tetrazol-5-ylthiomethyl, 1H-tetrazol-5-ylthioethyl,(1-methyl-1H-tetrazol-5-ylthio)-ethyl,2-methyl-1,3,4-thiadiazol-5-ylthiomethyl; lower alkoxycarbonylmethyl orlower alkoxycarbonylethyl, for example methoxycarbonylmethyl,ethoxycarbonylmethyl or methoxycarbonylethyl; cyanomethyl, cyanoethyl;or optionally protected aminomethyl, aminoethyl or aminopropyl.

A lower alkenyl radical R₁ contains 2 to 7, especially 2 to 4, carbonatoms, and is, for example, vinyl, allyl or but-2-enyl or but-3-enyl.Substituted lower alkenyl may carry the same substituents as substitutedlower alkyl and is, for example, 2-aminovinyl or 2-acylaninovinyl, suchas 2-acetylaminovinyl.

An optionally functionally modified carboxyl group R₁ is a free carboxylgroup or one of the, for example esterified or oxidated, carboxyl groupsmentioned under the groups --C(═O)--R₂ ^(A), such as loweralkoxycarbonyl, for example methoxycarbonyl ethoxycarbonyl ortert.-butoxycarbonyl; aryl-lower alkoxycarbonyl, such asbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl;aryloxycarbonyl, such as phenoxycarbonyl optionally substituted, forexample, by halogen, such as chlorine, by lower alkoxy, such as methoxy,or by nitro, such as phenoxycarbonyl, o-, m- or p-chlorophenoxycarbonyl,pentachlorophenoxycarbonyl, o-, m- or p-methoxyhenoxycarbonyl orp-nitrophenoxycarbonyl; or aminocarbonyl or substituted aminocarbonylsuch as aminocarbonyl mono- or disubstituted by, for example loweralkyl, for example methyl or ethyl.

A cycloalkyl radical R₁ has, for example, 3 to 7 carbon atoms and is,for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, whilsta cycloalkyllower alkyl radical R₁ has, for example, 4 to 7 carbon atomsand is, for example, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl or cyclohexylmethyl.

A cycloalkenyl radical R₁ is a corresponding cycloalkyl radical havingone or optionally two C--C double bonds, such as cyclohexenyl, forexample cyclohex-1-enyl, or cyclohexadienyl, for examplecyclohexa-1,4-dienyl.

A cycloalkyl-lower alkenyl radical or cycloalkenyl-lower alkyl radicalR₁ is, for example, cyclohexylvinyl or cyclohexylallyl, orcyclohexenylmethyl or cyclohexa-1,4-dienylmethyl respectively.

A phenyl or phenyl-lower alkyl radical R₁, for example a benzyl or 1- or2-phenylethyl radical, may be substituted, preferably in the aromaticradical, for example by lower alkyl, such as methyl or ethyl, by loweralkoxy, such as methoxy, or by halogen, such as fluorine or chlorine, oralso by nitro or amino.

A radical R₁ may alternatively represent a heterocyclic orheterocyclic-aliphatic radical bonded by a carbon atom and preferably ofaromatic nature, such as pyridyl, for example pyrid-2-yl, pyrid-3-yl orpyrid-4-yl; thienyl, for example thien-2-yl, or furyl, for examplefur-2-yl; a corresponding pyridyl-lower alkyl, thienyl-lower alkyl orfuryl-lower alkyl radicals, especially pyridylmethyl, thienylmethyl orfurylmethyl radicals.

A phenyl- or heterocyclyl-lower alkenyl radical R₁ is a lower alkenylradical substituted in the same manner as a corresponding lower alkylradical, for example phenylvinyl or furylallyl.

An etherified mercapto group R₁ is etherified by an optionallysubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic hydrocarbon radical having up to 18, especiallyup to 10 carbon atoms, or a heterocyclic radical and is optionallysubstituted lower alkylthio, lower alkenylthio, cycloalkylthio,cycloalkyl-lower alkylthio, phenylthio, phenyl-lower alkylthio orheterocyclylthio. Substituents of such radicals are, for example,optionally functionally modified, such as optionally etherified oresterified, hydroxy or mercapto, for example hydroxy, lower alkoxy, forexample methoxy or ethoxy, lower alkanoyloxy, for example acetoxy orpropionoxy, halogen, for example chlorine or bromine, or loweralkylthio, for example methylthio; or optionally functionally modifiedcarboxyl groups, such as carboxyl, lower alkoxycarbonyl, for examplemethoxycarbonyl or ethoxycarbonyl, carbamoyl or cyano; also nitro; oroptionally substituted amino, such as amino mono- or di-substituted suchas by lower alkyl, for example methyl or ethyl, or by acyl, such aslower alkanoyl, for example acetyl, or amino di-substituted by loweralkylene, for example by 1,4-butylene or 1,5-pentylene; or thesubstituents listed below in the case of the individual etherifiedmercapto groups R₁.

A lower alkylthio radical R₁ contains up to 7, especially up to 4,carbon atoms, and is, for example, methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, tert.-butylthio or pentylthio.Substituted lower alkylthio R₁ is, primarily, substituted methylthio,ethylthio or propylthio, the substituents standing in the 1-, 2- or3-position such as methoxymethylthio, ethoxymethylthio, methoxyethylthioor methoxypropylthio; lower alkanoyloxymethylthio, loweralkanoyloxyethylthio or lower alkanoyloxypropylthio, such asacetoxymethylthio, acetoxyethylthio or acetoxypropylthio;halomethylthio, haloethylthio or halopropylthio, for examplechloroethylthio or bromoethylthio, or chloropropylthio orbromopropylthio; lower alkoxycarbonylmethylthio or loweralkoxycarbonylethylthio, for example methoxycarbonylethylthio;cyanomethylthio; cyanoethylthio; or optionally protected, for exampleacetylated, aminomethylthio, aminoethylthio or aminopropylthio.

A lower alkenylthio radical R₁ contains 2 to 7, especially 2 to 4,carbon atoms and is especially 1-lower alkynylthio, for example,vinylthio, prop-1-enylothio, but-1-enylthio or pent-1-enylthio or also2-lower alkenylthio, for example allylthio. Substituted loweralkenylthio R₁ is especially substituted in the 2-position, wherein thesubstituents that chiefly come into consideration are lower alkoxy,lower alkanoyloxy and optionally protected amino. Thus R₁ is, forexample, 2-methoxyvinylthio, 2-acetoxyvinylthio, 2-acetylaminovinylthioor correspondingly substituted prop-1-enylthio.

A cycloalkylthio group R₁ has, for example, 3 to 7 carbon atoms, and is,for example, cyclopropylthio, cyclobutylthio, cyclopentylthio orcyclohexylthio.

A cycloalkyl-lower alkylthio radical R₁ has, for example, 4 to 7 carbonatoms and is, for example, cyclopropylmethylthio, cyclobutylmethylthio,cyclopentylmethylthio or cyclohexylmethylthio.

A phenylthio radical R₁ or a phenyl-lower alkylthio radical R₁, forexample a benzyl- or 1- or 2-phenylethylthio radical, may besubstituted, preferably in the aromatic radical, for example by loweralkyl, such as methyl or ethyl, by lower alkoxy, such as methoxy, byhalogen, such as fluorine or chlorine, or by nitro or amino.

Heterocyclically etherified mercapto groups R₁ are especially etherifiedby an optionally substituted heterocyclic radical that has 1 to 4 ringnitrogen atoms and optionally a further ring hetero atom selected fromoxygen and sulphur and that is bonded to the mercapto group by a ringcarbon atom.

Such heterocyclic radicals are especially optionally substituted, forexample by the substituents mentioned below, monocyclic, five-membereddiaza-, triaza-, tetraza-, thiaza-, thiadiaza-, thiatriaza-, oxaza- oroxadiaza-cyclic radicals of aromatic nature, or optionally substitutedmonocyclic six-membered aza- or diaza-cyclic radicals of aromatic orpartially saturated character.

Substituents of such heterocyclyl radicals are, inter alia, lower alkyl,especially methyl, as well as ethyl, n-propyl, isopropyl orstraight-chained or branched butyl: or lower alkyl substituted byhydroxy, as lower alkoxycarbonyl, sulpho, amidated sulphomono- ordi-lower alkylamino, acylamino, as lower alkanoylamino, or bysubstituted lower alkanoylamino, such as lower alkanoylamino substitutedby carboxy or halogen, for example, 2-hydroxyethyl, 2-acetoxyethyl,2-chloroethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl,2-ethoxycarbonylethyl, sulphomethyl, 2-sulphoethyl, sulphamylmethyl,2-sulphamylethyl, 2-aminoethyl, 2-dimethylaminoethyl, or2-acetylaminoethyl. Further substituents of the heterocyclic radical arecycloalkyl, for example cyclopentyl or cyclohexyl; aryl, such as phenyloptionally substituted by halogen, for example chlorine, or by nitro;aryl-lower alkyl, for example benzyl; or a heterocyclyl radical such asfuryl, for example fur-2-yl, thienyl, for example thien-2-yl, oroxazolyl, for example oxazol-2-yl or oxazol-5-yl; or functional groups,such as: halogen, for example fluorine, chlorine or bromine; optionallysubstituted amino such as amino optionally mono-substituted ordi-substituted by lower alkyl, for example, amino, methylamino ordimethylamino; acylamino, such as lower alkanoylamino or loweralkanoylamino substituted by halogen or carboxy, such as acetylamino,3-chloroprcpionylamino or 3-carboxypropionylanino; nitro; hydroxy; loweralkoxy, for example methoxy, ethoxy, n-butoxy or 2-ethylhexyloxy; oroptionally functionally modified carboxyl, such as carboxy, esterifiedcarboxy, such as lower alkoxycarbonyl, for example methoxycarbonyl orethoxycarbonyl, optionally substituted, for example N-mono- orN,N-di-lower alkylated carbamcyl, for example, N-methylcarbamoyl orN,N-dimethylcarbamoyl; or cyano; as well as oxo or oxido; wherein one ormore such substituents are present and these are bonded especially toring carbon atoms, but alternatively, especially lower alkyl and oxido,are bonded to ring nitrogen atoms.

Preferred heterocyclically etherified mercapto groups R₁ in which theheterocyclic radical is a corresponding monocyclic, five-memberedradical, are inter alia imidazolylthio, for example imidazol-2-ylthio;triazolylthio optionally substituted by lower alkyl and/or phenyl, forexample, 1H-1,2,3-triazol-4-ylthio, 1-methyl-1H-1,2,3-triazol-4-ylthio,1H-1,2,4-triazol-3-ylthio, 5-methyl-1H-1,2,4-triazol-3-ylthio,3-methyl-1-phenyl-1H-1,2,4-triazol-5-ylthio, 4,5-dimethyl-4H-1,2,4-triazol-3-ylthio or 4-phenyl -4H-1,2,4-triazol-3-ylthio;especially tetrazolylthio optionally substituted as stated, for example1H-tetrazol-5-ylthio, 1-methyl-1H-tetrazol-5-ylthio,1-carboxymethyl-1H-tetrazol-5-ylthio,1-(2-carboxyethyl)-1H-tetrazol-5-ylthio, 1-sulphomethyl-1H-tetrazol-5-ylthio, 1-(2-sulphoethyl)-1H-tetrazol-5-ylthio,1-(2-dimethylaminoethyl)1H-tetrazol-5-ylthio,1-phenyl-1H-tetrazol-5-ylthio or1-(4-chlorophenyl)-1H-tetrazol-5-ylthio; thiazolylthio orisothiazolylthio optionally substituted by lower alkyl or thienyl, forexample thiazol-2-ylthio, 4-(thien-2-yl)-thiazol-2-ylthio,4,5-dimethylthiazol-2-ylthio, isothiazol-3-ylthio, isothiazol-4-ylthioor isothiazol-5-ylthio; especially thiadiazolylthio optionallysubstituted as stated, for 5-ylthio, 1,3,4-thiadiazol-2-ylthio,2-methyl-1,3,4-thiadiazol-5-ylthio 2-(3-carboxypropionylamino)-1,3,4-thiadiazol-5-ylthio, 1,2,4-thiadiazol-5-ylthio or1,2,5-thiadiazol-3-ylthio; thiatriazolylthio, for example1,2,3,4-thiatriazol-5-ylthio; oxazolylthio or isoxazolylthio optionallysubstituted as stated, for example oxazol-5-ylthio,4-methyloxoazol-5-ylthio, oxazol-2-ylthio, 4,5-diphenyloxazol-2-ylthioor 3-methylisoxazol-5-ylthio; or oxadiazolylthio optionally substitutedas stated, for example 1,2,4-oxadiazol-5-ylthio,2-methyl-1,3,4-oxadiazol-5-ylthio, 2-phenyl-1,3,4-oxadiazol-5-ylthio,5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ylthio or 2-(thien-2-yl)-1,3,4-oxadiazol-5-ylthio.

Preferred heterocyclically etherified mercapto groups R₁, in which theheterocyclic radical is a corresponding monocyclic, six-membered radicalor a corresponding partially saturated radical, are, inter alia,1-oxidopyridylthio, optionally substituted by halogen, for example1-oxidopyrid-2-ylthio or 4-chloro-1-oxidopyrid-2-ylthio; pyridazinylthiooptionally substituted by hydroxy, for example3-hydroxypyridazin-6-ylthio; N-oxidopyridazinylthio optionallysubstituted by lower alkyl, lower alkoxy or halogen, for example2-oxidopyridazin-6-ylthio, 3-chloro-1-oxidopyridazin-6-ylthio,3-methyl-2-oxidopyridazin-6-ylthio, 3-methoxy-1-oxidopyridazin-6-ylthio,3-ethoxy-1-oxidopyridazin- 6-ylthio,3-n-butoxy-1-oxidopyridazin-6-ylthio or3-(2-ethylhexyloxy)-1-oxidopyridazin-6-ylthio; or2-oxo-1,2-dihydropyrimidinylthio optionally substituted by lower alkyl,amino, di-lower alkylamino 4-ylthio,6-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthio,5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthio,6-amino-2-oxo-1,2-dihydropyrimidin-4-ylthio,6-dimethylamino-2-oxo-1,2-dihydropyrimidin-4-ylthio,5-carboxy-2-oxo-1,2-dihydropyrimidin-4-ylthio or6-carboxy-2-oxo-1,2-dihydropyrimidin-4-ylthio.

A protected carboxyl group of the formula --C(═O)--R₂ ^(A) is especiallyan esterified carboxyl group in which R₂ ^(A) represents a hydroxy groupetherified by an organic radical or an organic silyl or stannyl group.Organic radicals, also as substituents in organic silyl or stannylgroups, are aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic or araliphatic radicals, especially optionally substitutedhydrocarbon radicals of this type, and heterocyclic orheterocyclic-aliphatic radicals, preferably having up to 18 carbonatoms.

An etherified hydroxy group R₂ ^(A) forms together with the carbonylgrouping an esterified carboxyl group that can preferably be readilysplit, for example by reduction, such as by hydrogenolysis, or bysolvolysis, such as acid hydrolysis or, especially, basic or neutralhydrolysis, oxidatively, or under physiological conditions, or anesterified carboxyl group that is readily convertible into anotherfunctionally modified carboxyl group, such as into another esterifiedcarboxyl group or into a hydrazinocarbonyl group. Such a group R₂ ^(A)is, for example, 2-halo-lower alkoxy, in which the halogen preferablyhas an atomic weight of more than 19, for example 2,2,2-trichloroethoxyor 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy which may readilybe converted into the latter, or 2-lower alkylsulphonyl-lower alkoxy,for example, 2-methylsulphonylethoxy. The group R₂ ^(A) is optionallysubstituted hydrocarbon radicals, especially saturated aliphatic oraromatic hydrocarbon radicals, such as lower alkyl, for example methyl,and/or phenyl, or is a methoxy group mono-substituted by an unsaturatedaliphatic hydrocarbon radical, such as lower alkenyl, for example1-lower alkenyl, such as vinyl, by a carbocyclic aryl group havingelectron-donating substituents, or by a heterocyclic group of aromaticnature having oxygen or sulphur as ring member. Examples of such groupsR₂ ^(A) are tert.-lower alkoxy, for example tert.-butoxy ortert.-pentoxy; optionally substituted diphenylmethoxy, for examplediphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy; lower alkenyloxy,especially 2-lower alkenyloxy, for example allyloxy; loweralkoxyphenyl-lower alkoxy, for example lower alkoxybenzyloxy, such asmethoxybenzyloxy (in which methoxy is especially in the 3-, 4- and/or5-position), especially 3- or 4-methoxybenzyloxy or3,4-dimethoxybenzyloxy; or, above all, nitrobenzyloxy, for example,4-nitrobenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitrobenzyloxy; orfurfuryloxy, such as 2-furfuryloxy. The group R₂ ^(A) is furthermore a2-oxoethoxy group that is optionally substituted in the 2-position bylower alkyl, such as methyl, by lower alkoxy, such as methoxy or ethoxy,by aralkyl, such as benzyl, or by aryl, such as phenyl, and issubstituted in the 1-position by lower alkyl, such as methyl, loweralkoxycarbonyl, such as methoxycarbonyl, lower alkylcarbonyl, such asmethylcarbonyl, aralkylcarbonyl, such as benzylcarbonyl, orarylcarbonyl, such as benzoyl. Thus R₂ ^(A) represents, for example,acetonyloxy, phenacyloxy, 2,4-dioxo-3-pentoxy,1-methoxycarbonyl-2-oxopropoxy or 1-ethoxycarbonyl-2-oxopropoxy. Thegroup R₂ ^(A) is alternatively a 2-cyanoethoxy group that is optionallysubstituted in the 1- and/or in the 2-position, for example by loweralkyl, such as methyl, or by aryl, such as optionally substitutedphenyl, and represents, for example, 2-cyanoethoxy or2-cyano-2-phenylethoxy. R₂ ^(A) is alternatively a2-(S₁)(S₂)(S₃)-silylethoxy group, in which each of the substituents S₁,S₂ and S₃ independently of one another represents an optionallysubstituted hydrocarbon radical and the individual radicals may belinked by a single C--C bond A hydrocarbon radical S₁, S₂, S₃ is, forexample, an alkyl radical, a cycloalkyl radical or an aryl radical,preferably such a radical having a maximum of 12 carbon atoms, whereinthe radical of one kind may be substituted by a radical of a differentkind, or by lower alkoxy, such as methoxy, or by halogen, such asfluorine or chlorine; and is especially lower alkyl having up to 7,preferably up to 4, carbon atoms, such as methyl, ethyl, propyl or butylcycloalkyl having up to 7 carbon atoms, such as cyclopropyl orcyclohexyl; cycloalkylalkyl, such as cyclopentylmethyl; aryl having upto 10 carbon atoms, such as phenyl, tolyl or xylyl; or aryl-lower alkyl,such as benzyl or phenylethyl. Radicals R₂ ^(A) of this kind to be givenspecial mention are 2-tri-lower alkylsilylethoxy, such as2-trimethylsilylethoxy or 2-(dibutylmethylsilyl)-ethoxy, and2-triarylsilylethoxy, such as 2-triphenylsilylethoxy.

R₂ ^(A) may alternatively be 2-oxa- or 2-thia-cycloalkoxy or-cycloalkenyloxy having 5-7 ring members, such as 2-tetrahydrofuryloxy,2-tetrahydropyranyloxy or 2,3-dihydro-2-pyranyloxy or a correspondingthia group, or R₂ ^(A) forms together with the --C(═O)-- grouping anactivated ester group and is, for example, nitrophenoxy, for example4-nitrophenoxy or 2,4-dinitrophenoxy, or polyhalo-phenoxy, for examplepentachlorophenoxy. R₂ ^(A) may, however, alternatively be lower alkoxy,for example methoxy or ethoxy.

An organic silyloxy or organic stannyloxy group R₂ ^(A) is especially asilyloxy or stannyloxy group substituted by 1 to 3 optionallysubstituted hydrocarbon radicals, preferably having up to 18 carbonatoms. It contains as substituents preferably optionally substituted,for example by lower alkoxy, such as methoxy, or by halogen, such aschlorine, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbonradicals, such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl orphenyl-lower alkyl and represents especially tri-lower alkylsilyloxy,for example, trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyloxy,for example, chloromethoxymethylsilyloxy; or tri-lower alkylstannyloxy,for example tri-n-butylstannyloxy.

The group R₂ ^(A) may alternatively be an etherified hydroxy group thattogether with the carbonyl grouping --C(═O)-- forms an esterifiedcarboxyl group that can be split under physiological conditions.

These ester groups impart to the inherently active carboxylic acidsimproved absorption for oral administration and/or prolonged activity.Numerous such ester groups are known in the field of penicillins andcephalosporins. There may be mentioned, for example, --C(═O)--R₂ ^(A)groups in which R₂ ^(A) represents a methoxy group substituted by acyl,acyloxy, acylthio, acylamino or etherified hydroxy and optionally afurther organic radical, in which the methyl group may be bonded to thecarbonyl of the acyl group also by means of a bridge containing carbon,or represents a 2-amino-aliphatyloxy group. In such groups acylrepresents the radical of an organic carboxylic acid having up toapproximately 18 carbon atoms, and is, for example, optionallysubstituted alkanoyl, cycloalkanoyl, aroyl, heterocyclylcarbonyl, forexample also the heterocyclylcarbonyl radical of a carboxylic acid ofthe formula I, or of a biologically active penam-3- orcephem-4-carboxylic acid, or is the acyl radical of a semi-seter ofcarbonic acid. Etherified hydroxy in the methoxy group is etherified bya hydrocarbon radical, especially by lower alkyl. The organic radicalthat optionally additionally substitutes the methoxy group has up to 7carbon atoms and is especially lower alkyl, such as methyl, or aryl,such as phenyl. The said carbon bridge contains one to three, especiallytwo, carbon atoms, so that a lactone, especially a γ-lactone, ispresent. The aliphatyl group in the said 2-aminoaliphatyl group may beof aliphatic or cycloaliphatic nature and is saturated or unsaturated.The 2-amino group is preferably substituted by alkylene containing twolower alkyl groups or optionally an oxa group. In such ester groups--C(═O)--R₂ ^(A) that can be split physiologically, R₂ ^(A) is, forexample, lower alkanoyloxymethoxy, for example acetoxymethoxy orpivaloyloxymethoxy; amino-lower alkanoyloxymethoxy, especiallyα-amino-lower alkanoyloxymethoxy, for example glycyloxymethoxy,L-valyloxymethoxy, L-leucyloxymethoxy; lower alkoxycarbonyloxymethoxy or1-lower alkoxycarbonyloxyethoxy, for example 1-ethoxycarbonyloxyethoxy;lower alkanoylthiomethoxy, for example acetylthiomethoxy orpivaloylthiomethoxy; lower alkanoylaminomethoxy, in which lower alkanoylmay optionally be substituted by halogen, such as chlorine, for exampleacetylaminomethoxy or 2,2-dichloroacetylaninomethoxy; aroylaminomethoxy,for example benzoylaminomethoxy; or, as an example of R₂ ^(A) containinglactone, phthalidyloxy. The etherified hydroxymethoxy group R₂ ^(A) is,for example, lower alkoxymethoxy, especially methoxymethoxy. A2-aminoaliphatyloxy group R₂ ^(A) is, for example, a 2-amino-loweralkoxy group, such as a 2-aminoethoxy group, in which amino issubstituted by two lower alkyl groups or by alkylene optionallycontaining an oxa group, and represents, for example,2-dimethylaminoethoxy, 2-diethylaminoethoxy or 2-(1-morpholino)ethoxy,or 2-aminocycloalkyloxy, for example 2-dimethylaminocyclohexyloxy.

A radical R₂ ^(A) forming with a --C(═O)-- grouping an optionallysubstituted hydrazinocarbonyl group is, for example, hydrazino or2-lower alkylhydrazino, for example 2-methylhydrazino.

Preferred groups R₂ ^(A) are those that can be converted into a freehydroxy group under neutral, basic or physiological conditions.

Salts are especially those of compounds of the formula I with an acidgrouping such as a carboxyl group, or alternatively ahydroxysulphonyloxy group or sulpho group, especially metal or ammoniumsalts, such as alkali metal and alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts; as well as ammonium saltswith ammonia or suitable organic amines, especially aliphatic,cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary,secondary or tertiary mono-, di- or polyamines, or heterocyclic basesbeing suitable for the salt formation, such as lower alkylamines, forexample triethylamine; hydroxy-lower alkylamines, for example2-hydroxyethylamine, di-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)-amine; basic aliphatic esters of carboxylic acids,for example 4-aminobenzoic acid 2-diethylaminoethyl ester; loweralkyleneamines, for example 1-ethylpiperidine; cycloalkylamines, forexample bicyclohexylamine; or benzylamines, for exampleN,N'-dibenzylethylenediamine; and also, bases of the pyridine type, forexample pyridine, collidine or quinoline. Compounds of the formula Ithat have a basic group may likewise form acid addition salts, forexample with inorganic acids, such as hydrochloric acid, sulphuric acidor phosphoric acid, or with suitable organic carboxylic or sulphonicacids, for example trifluoroacetic acid or p-toluenesulphonic acid.Compounds of the formula I having an acid and a basic group may alsooccur in the form of inner salts, that is in the zwitterion form.Pharmaceutically acceptable salts are preferred.

In the penem compounds of the formula I the two asymmetric carbon atomsin the 5- and 6-positioned may occur in the R-, the S- or the racemicR,S-configuration. Preferred are the compounds in which theconfiguration of the 5-carbon atom corresponds to that of naturalpenicillin (5R-configuration). The substituents in the 5- and6-positions may be in the cis- or trans-position in relation to oneanother.

The compounds of the present invention have valuable pharmacologicalproperties or may be used as intermediate for the manufacture ofcompounds having such properties. Compounds of the formula I in whichR_(a) and R₁ have the meanings given above and R₂ represents hydroxy oran etherified hydroxy group R₂ ^(A) forming together with the carbonylgroup an esterified carboxyl group that can be readily split preferablyunder physiological conditions, or pharmacologically acceptable salts ofsuch compounds having salt-forming groups have anti-bacterialactivities. They inhibit, for example, the growth, of gram-positive andgram-negative bacteria, such as Staphylococcus aureus andpenicillin-resistant Staphylococcus aureus, Escherichia coli, Proteusvulgaris, Pseudomonas aeruginosa and Pseudomonas aeruginosa R. Using thecompounds of the formula I according to the invention in the disc-platetest with the specific bacteria with a 0.5% strength solution on filterpaper (6 mm diameter) inhibiting zones of approximately 12 to 33 mmdiameter are found.

Penicillin V tested analogously at the same time, in the case ofpenicillin-sensitive Staphylococcus aureus bacteria causes inhibitingzones of 29 to 33 mm diameter and in the case of penicillin-resistantbacteria inhibiting zones of a maximum of 9 to 12 mm. Neither PenicillinV nor Penicillin G is effective against Pseudomonas aeruginosa.

The anti-bacterial activity in vitro may also be ascertained in the AgarDilution Test (according to Ericsson) in which against gram-positive andgram-negative cocci MIC values of 0.06 to 8 mcg/ml are ascertained andagainst gram-negative bacilli, such as entero bacteria, Pseudomonas andHaemophilus, MIC values of from 2 to 128 mcg/ml are ascertained

In vivo, in the systemic infection of mice with Streptococcus pyoqenesAronson, on subcutaneous administration of the compounds according tothe invention ED₅₀ values of approximately ≦1 to approximately 50 mg/kgresult.

Attention is drawn in particular to the activity against Pseudomonasaeruginosa.

The compounds inhibit β-lactamases and have a synergistic effect incombination with other β-lactam antibiotics.

These new compounds, especially the preferred ones, or theirpharmacologically acceptable salts, may therefore be used, alone or incombination with other antimicrobica, for example, in the form ofantibiotically-active preparations, in the treatment of correspondingsystemic or organ infections, as fodder additives, for preservingfoodstuffs or as disinfectants.

Compounds of the formula I, in which R_(a) and R₁ have the meaningsgiven above, in which functional groups optionally present may beprotected, and in which R₂ represents a radical R₂ ^(A) forming togetherwith the --C(═O)-- grouping a protected carboxyl group that canpreferably be readily split, wherein a carboxyl group protected in thismanner is different from a carboxyl group that can be splitphysiologically, are valuable intermediates that can be converted in asimple manner, for example as described below, into the above-mentioned,pharmacologically active compounds.

The invention relates especially to the 2-penem compounds of the formulaI, in which R_(a) represents lower alkyl, hydroxy-lower alkyl,especially 1-hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkanoyloxy-lower alkyl, hydroxysulphonyloxy-lower alkyl in salt form,especially 1-hydroxysulphonyloxy-lower alkyl, hydroxy, lower alkoxy,lower alkanoyloxy or lower alkanoyloxy substituted by phenoxy, hydroxy,halogen, amino or cyano, or phenyl-lower alkanoyloxy or phenyl-loweralkanoyloxy substituted by hydroxy or amino; R₁ represents hydrogen,lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkanoyloxy-lower alkyl, lower alkylthio-lower alkyl,heterocyclylthio-lower alkyl, amino-lower alkyl, acylamino-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, phenyl-loweralkyl, phenyl: phenyl substituted by lower alkyl, lower alkoxy, hydroxy,halogen, nitro or by amino; furyl, thienyl, pyridyl; lower alkenylthioor lower alkylthio optionally substituted by hydroxy, lower alkoxy,lower alkanoyloxy, lower alkylthio, lower alkoxycarbonyl, carbamoyl,cyano, nitro, amino or by amino mono-substituted or di-substituted bylower alkyl or lower alkanoyl; or triazolylthio, tetrazolylthio,thiazolylthio, thiatriazolylthio, thiadiazolylthio, oxazolylthio oroxadiazolylthio, in which the heterocyclic rings may optionally besubstituted, for example by lower alkyl, N,N-di-lower alkylamino-loweralkyl, carboxy-lower alkyl, sulpho-lower alkyl, amino, carboxy-loweralkanoylamino or by carbamoyl; and R₂ represents hydroxy, a hydroxygroup etherified by an easily, especially physiologically, splittableorganic radical or an organic silyl or stannyl group, or an optionallysubstituted hydrazino group R₂ ^(A), and relates to salts of suchcompounds with salt-forming groups.

In a 2-penem compound of the formula I or in a salt of such a compoundhaving salt-forming groups, R_(a) especially represents lower alkylhaving up to 4 carbon atoms, for example methyl, ethyl, propyl or butyl;hydroxy-lower alkyl especially 1-hydroxylower alkyl, having up to 4carbon atoms, for example hydroxymethyl, hydroxyethyl or hydroxypropyl;lower alkoxy-lower alkyl, especially 1-lower alkoxy-lower alkyl, inwhich lower alkyl contains up to 4 carbon atoms, for example1-methoxymethyl, 1-methoxyethyl or methoxypropyl; loweralkanoyloxy-lower alkyl, especially 1-lower alkanoyloxy-lower alkyl, inwhich lower alkanoyloxy and lower alkyl each contain up to 4 carbonatoms, for example acetoxymethyl, propionoxymethyl or 1-acetoxyethyl;hydroxysulphonyloxy-lower alkyl in salt form, in which lower alkylcontains up to 4 carbon atoms, especially 1-hydroxysulphonyloxy-loweralkyl, for example hydroxysulphonyloxymethyl, 1-hydroxysulphonyloxyethylor 1-hydroxysulphonyloxypropyl; hydroxy; lower alkoxy containing up to 4carbon atoms, for example methoxy, ethoxy, propoxy or butoxy; loweralkanoyloxy having up to 4 carbon atoms, for example formyloxy, acetoxyor propionoxy, or such a lower alkanoyloxy substituted by phenoxy,hydroxy, halogen, amino or cyano, for example phenoxyacetoxy,hydroxyacetoxy, haloacetoxy, aminoacetoxy or cyanoacetoxy; phenyl-loweralkanoyloxy, in which lower alkanoyloxy contains up to 4 carbon atoms,for example phenylacetoxy, or phenyl-lower alkanoyloxy substituted byhydroxy or amino, in which lower alkanoyl contains up to 4 carbon atoms,for example hydroxyphenylacetoxy or aminophenylacetoxy, in which hydroxyor amino is preferably in the p-position, or α-hydroxyphenylacetoxy orα-aminophenylacetoxy; R₁ especially represents hydrogen; lower alkylhaving up to 4 carbon atoms, for example methyl, ethyl, propyl or butyl;hydroxy-lower alkyl, especially ω-hydroxy-lower alkyl, having up to 4carbon atoms, for example hydroxymethyl, hydroxyethyl or hydroxypropyl;lower alkoxy-lower alkyl, especially ω-lower alkoxy-lower alkyl, inwhich lower alkoxy and lower alkyl contain up to 4 carbon atoms, forexample methoxymethyl, methoxyethyl or methoxypropyl; loweralkanoyloxy-lower alkyl, especially ω-lower alkanoyloxy-lower alkyl, inwhich lower alkanoyloxy and lower alkyl each contain up to 4 carbonatoms, for example acetoxymethyl, acetoxyethyl or acetoxypropyl; loweralkylthio-lower alkyl, especially ω-lower alkylthio-lower alkyl, inwhich lower alkyl contains up to 4 carbon atoms, for examplemethylthiomethyl, tert.-butylthiomethyl, methylthioethyl ormethylthiopropyl; heterocyclylthio-lower alkyl, in which lower alkylcontains up to 4 carbon atoms and heterocyclyl represents afive-membered aromatic diaza-, thiaza-, tetraza-, thiaza-, thiadiaza-,thiatriaza-, oxaza- or oxadiaza-cyclic radical optionally substituted bylower alkyl, such as methyl, carboxy-lower alkyl, for examplecarboxymethyl or 1- or 2-carboxyethyl, optionally N-substitutedamino-lower alkyl, such as di-lower-alkylamino-lower alkyl, for exampledimethylaminoethyl, sulpho-lower alkyl in salt form, for examplesulphomethyl or 1- or 2-sulphoethyl in the form of a sodium salt, forexample imidazol-2-ylthiomethyl, 1,2,3-triazol-4-ylthiomethyl,1-methyl-1H-1,2,3-triazol-4-ylthiomethyl, 1H-tetrazol-5-ylthiomethyl,1-methyl-1H-tetrazol-5-ylthiomethyl,1-carboxymethyl-1H-tetrazol-5-ylthiomethyl,1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthiomethyl, 1-sodiumsulphomethyl-1H-tetrazol-5-ylthiomethyl or2-methyl-1,3,4-thiadiazol-5-ylthiomethyl or an ethyl radicalcorrespondingly substituted in the 2-position; amino-lower alkyl,especially ω-amino-lower alkyl in which lower alkyl contains up to 4carbon atoms, for example aminomethyl, aminoethyl or aminopropyl;acylamino-lower alkyl, in which acyl is lower alkanoyl or a substitutedoxycarbonyl group that can be used as an amino-protective group, forexample acetylaminomethyl, acetylaminoethyl, acetylaminopropyl ortert.-butyl-, 2,2,2-trichloroethyl-, diphenylmethyl- orp-nitrobenzyloxycarbonylaninomethyl, -ethyl or -propyl; carboxy-loweralkyl, in which lower alkyl contains up to 4 carbon atoms and carboxy isespecially carbonyl-lower alkyl each contain up to 4 carbon atoms, forexample, methoxy-, ethoxy- or tert.-butoxycarbonylmethyl or -ethyl; orphenyl-lower alkyl, in which lower alkyl contains up to 4 carbon atoms,for example benzyl, phenylethyl or phenylpropyl; phenyl; hydroxyphenyl;aminophenyl; furyl, thienyl or pyridyl, such as fur-2-yl; thien-2-yl,pyrid-2-yl; pyrid-3-yl; pyrid-4-yl; lower alkylthio, for examplemethyl-, ethyl- or propylthio, lower alkenylthio, for example vinylthioor allylthio, or lower alkylthio or lower alkenylthio substituted,especially in the Ω-position, by amino, mono- or di-lower alkylamino orlower alkanoyl amino, for example 2-aminoethylthio,2-methylaminoethylthio, 2-dimethylaminoethylthio,2-acetylaminoethylthio, 3-aminopropylthio, 3-methylaminopropylthio,3-dimethylaminopropylthio or 3-acetylaminopropylthio,2-acetylaminoethylthio; tetrazolylthio or thiadiazolthio optionallysubstituted by lower alkyl, sulfo-lower alkyl, carboxy-lower alkyl, orby di-lower alkylamino-lower alkyl, especially1-methyl-1H-tetrazol-5-ylthio, 1-sulphomethyl-1H-tetrazol-5-ylthio,1-carboxymethyl-1H-tetrazol-5-ylthio,1-(2dimethylaminoethyl)-1H-tetrazol-5-ylthio;2-methyl-1,3,4-thiadiazol-5-ylthio or 1,3,4-thiadiazol-1-ylthio; and R₂especially represents hydroxy, optionally α-polybranched lower alkoxy,for example, methoxy or tert.-butoxy; or 2-halo-lower alkoxy, forexample 2,2,2-trichloroethoxy, 2-iodoethoxy, or 2-chloroethoxy or2-bromoethoxy readily convertible into the 2-iodoethoxy; or phenacyloxy;1-phenyl-lower alkoxy having 1-3 phenyl radicals optionally substitutedby lower alkoxy and/or nitro, for example 4-methoxybenzyloxy,4-nitrcbenzyloxy, 2-nitro-4,5-dimethoxybenzyloxy, diphenylmethoxy,4,4'-dimethoxydiphenylmethoxy or trityloxy; acetonyloxy; 2-cyanoethoxy;2-tri-lower alkylsilylethoxy, for example 2-trimethylsilylethoxy; loweralkancyloxymethoxy, for example acetoxymethoxy or pivaloyloxymethoxy;αamino-lower alkanoyloxymethoxy, for example glycyloxymethoxy,phthalidyloxy, pentachlorophenoxy; also tri-lower alkylsilyloxy, forexample trimethylsilyloxy; and lower alkenyloxy, such as 2-loweralkenyloxy, for example allyloxy.

The invention relates especially to 2-R₁ --6-R₂ --2-penem-3-carboxylicacid compounds in which

R_(a) represents lower alkyl having up to 4 carbon atom, especiallymethyl, ethyl, propyl, isopropyl, or butyl; 1-hydroxy-lower alkyl havingup to 4 carbon atom, especially hydroxymethyl, 1-hydroxmethyl;1-hydroxypropyl or 1-hydroxyisopropyl; phenyl-lower alkyl having up to10 carbon atoms, especially benzyl; phenoxy-lower alkanoyloxy having upto 10 carbon atoms, especially phenoxyacetoxy; or lower alkoxy having upto 4 carbon atoms, especially methoxy;

and R₁ represents hydrogen; lower alkyl having up to 4 carbon atoms,especially methyl: amino- lower alkyl, especially ω-amino-lower alkyl,in which lower alkyl contains up to 4 carbon atoms, for exampleaminomethyl, aminoethyl or aminopropyl; acylamino-lower alkyl, in whichacyl is lower alkanoyl or a substituted oxycarbonyl group that can beused as an amino-protective group, for example acetylaminomethylacetylaminoethyl, acetylaminopropyl or tert.-butyl-,2,2,2-trichloroethyl-, diphenylmethyl- orp-nitrobenzyloxycarbonylaminomethyl, -ethyl or -propyl; lower alkylthio,especially ethylthio; lower alkylthio or lower alkenylthio substituted,especially in the Ω-position, by amino, mono- or di-lower alkylamino orlower alkanoylamino, for example 2-aminoethylthio,2-methylaminoethylthio, 2-dimathylaminoethylthio,2-acetylaminoethylthio, 3-aminopropylthio, 3-methylamincpropylthio,3-dinethylaminopropylthio or 3-acetylaninopropylthio,2-acetylaninovinylthio, 1-methyl-1H-tetrazol-5-ylthio,1-(2-dimethylaminoethyl)-1H-tetrazol-5-ylthio,2-methyl-1,3,4-thiadiazol-5-ylthio or 1,3,4-thiadiazol-2-ylthio; and tothe esters, especially the esters that can be split under neutral orbasic conditions, such as nitrobenzyl esters, for example 4-nitrobenzyl,diphenylmethyl, pentachlorophenyl, acetonyl, 2-cyanoethyl or2-trimethylsilylethyl ester, and to esters of such compounds that can besplit under physiological conditions, and to the salts, especially thepharmacologically acceptable salts, of such compounds havingsalt-forming groups,

The invention relates especially to the compounds of the formula Imentioned in the Examples, to the salts thereof, especially the-pharmaceutically acceptable salts, and to the new starting materialsand intermediates that can be used for their manufacture.

On account of its particularly good antibacterial activity,6-ethyl-2-(3-aminopropyl)-2-penem 3-carboxylic acid, especially thecorresponding 5R-compound, and the pharmacologically acceptable saltsand physiologically split-table esters are to be given specialattention.

The new compounds are produced by ring closing an ylid compound of theformula ##STR5## in which R_(a), R₁ and R₂ ^(A) have the meanings given,wherein the functional groups in these radicals are preferably presentin protected form, Z represents oxygen or sulphur,

and in which

X.sup.⊕ represents either a phosphonio group substituted three times ora phosphono group esterified twice, together with a cation

and, if desired or necessary, converting the protected carboxyl group ofthe formula --C(═O)--R₂ ^(A) in a compound of the formula I obtainedinto the free or into a different protected carboxyl group, and/or, ifdesired, in a compound of the formula I obtained, converting a groupR_(a) and/or R₁ within the definition into a different group R_(a)and/or R₁, and/or, if desired, converting a compound obtained having asalt-forming group into a salt, or a salt obtained into the freecompound or into a different salt, and/or, if desired, separating amixture of isomeric compounds obtained into the individual isomers.

In the starting material of the formula II R_(a), R₁ and R₂ ^(A) haveespecially the preferred meanings, wherein functional groups are usuallypresent in the protected form, amino, for example, is present in theform of the nitro or azido group.

In a starting material of the formula II, R₂ ^(A) preferably representsan etherified hydroxy group forming together with the --C(═O)-groupingan esterified carboxyl group that can readily be split, especially undermild conditions, wherein functional groups that are optionally presentin a carboxyl protective group R₂ ^(A) may be protected in a mannerknown per se, for example as indicated above. A group R₂ ^(A) is interalia lower alkoxy, especially α-polybranched lower alkoxy, for examplemethoxy or tert.-butoxy; lower alkenyloxy, especially 2-loweralkenyloxy, for example allyloxy; or 2-halo-lower alkoxy, for example2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy; 2-loweralkylsulphonyllower alkoxy, for example 2-methylsulphonylethoxy; or anoptionally substituted, such as lower alkoxy, for example methoxy-, ornitro-containing, 1-phenyl-lower alkoxy group, such as diphenylmethoxyor benzyloxy optionally substituted, for example as mentioned, forexample benzyloxy, 4-methoxybenzyloxy,4-nitrobenzyloxy, diphenylmethoxyor 4,4'-dimethoxydiphenylmethoxy: pentachlorophenoxy; acetonyloxy;2-cyanoethoxy; a 2-(S₁)(S₂)(S₃)-silylethoxy group, such as2-trimethylsilylethoxy, 2-(dibutylmethylsilyl)-ethoxy or2-triphenylsilylethoxy; also an organic silyloxy or stannyloxy group,such as tri-lower alkylsilyloxy, for example trimethylsilyloxy; or oneof the mentioned etherified hydroxy groups that can be splitphysiologically.

The group X.sup.⊕ in the starting material of the formula II is one ofthe phosphonio or phosphono groups customary in the Wittig condensationreaction, especially a triaryl-, for example triphenyl-, or triloweralkyl-, for example tributylphosphonio group, or a phosphono groupesterified twice by lower alkyl, for example ethyl, wherein the symbolX.sup.⊕ in the case of the phosphono group additionally includes thecation of a strong base, especially a suitable metal, for example alithium sodium or potassium, ion. Preferred as group X.sup.⊕ is in onecase triphenylphosphonio and in the other case diethylphosphono togetherwith an alkali metal ion, for example a sodium ion.

In phosphonio compounds of the formula II, which in the isomeric yleneform are alternatively called phosphorane compounds, the negative chargeis neutralised by the positively charged phosphonio group. In phosphonocompounds of the formula II, which in their isomeric form canalternatively be called phosphonate compounds, the negative charge isneutralised by the cation of a strong base, which cation, depending onthe method of production of the phosphono starting material, may be, forexample, an alkali metal ion, for example, a sodium, lithium orpotassium ion. The phosphonate starting substances are therefore used assalts in the reaction.

Formula II shows the starting material in the form in which the ringclosure takes place. Normally the corresponding phosphoranylidenecompound of the formula ##STR6## in which X₁ represents atri-substituted, especially a triaryl-, for example triphenyl-, or atri-lower alkyl-, for example tri-n-butyl-phosphoranylidene radical, orthe corresponding phosphono compound of the formula ##STR7## which X₂represents a phosphono-, especially a dialkylphosphono-, for example adiethylphosphono group, is used, wherein a phosphono starting materialof the formula IIB is converted into the form suitable for the ringclosure that is into the compound of the formula II, by treating with asuitable basic reagent, such as an inorganic base, for example an alkalimetal carbonate, such as sodium or potassium carbonate, or with anorganic base, such as a tri-lower alkylamine, for example triethylamine,or a cyclic base of the amidine type, such as an appropriatediaza-bicycloalkene compound, for example1,5-diaza-bicyclo[5,4,0]undec-5-ene.

Preferred starting materials are the phosphoranylidene compounds of theformula IIA.

The ring closure can take place spontaneously, that is to say during theproduction of the starting materials, or by heating, for example in atemperature range of approximately 30° C. to approximately 160° C.,preferably of approximately 50° C. and approximately 100° C.

The reaction is preferably carried out in the presence of a suitableinert solvent, such as in an aliphatic, cycloaliphatic or aromatichydrocarbon, for example hexane, cyclohexane, benzene, toluene, xyleneor mesitylene; a halogenated hydrocarbon, for example methylenechloride; an ether, for example diethyl ether; a lower alkylene glycoldi-lower alkyl ether, for example dimethoxyethane or diethylene glycoldimethyl ether, or a cyclic ether, for example dioxan ortetrahydrofuran; a carboxylic acid amide, for example dimethylformamide;a di-lower alkyl sulphoxide, for example dimethylsulphoxide; or a loweralkanol, for example methanol, ethanol or tert.-butanol; or in a mixturethereof, and, if necessary, in an inert gas atmosphere, for example anargon or nitrogen atmosphere.

In a compound of the formula I obtainable according to the inventionhaving a protected, especially an esterified, carboxyl group of theformula --C(═O)--R₂ ^(A), the latter can be converted in a manner knownper se, for example depending on the type of protective group, into thefree carboxyl group. For example, a carboxyl group esterified by asuitable 2-halo-lower alkyl group, an arylcarbonylmethyl group or a4-nitrobenzyl group can be converted into the free carboxyl group forexample by treating with a chemical reducing agent, such as a metal, forexample zinc, or a reducing metal salt, such as a chromium(II) salt, forexample chromium(II) chloride, usually in the presence of ahydrogen-yielding agent, which together with the metal enables nascenthydrogen to be produced, such as an acid, especially acetic or formicacid, or an alcohol, wherein water is preferably added; a carboxyl groupesterified by an arylcarbonylmethyl group can be converted into the freecarboxyl group by treating with a nucleophilic, preferably salt-formingreagent, such as sodium thiophenolate or sodium iodide; and also acarboxyl group esterified by 4-nitrobenzyl can be converted into thefree carboxyl group by treating with an alkali metal dithionite, forexample sodium dithionite. A carboxyl group esterified by a 2-loweralkylsulphonyl-lower alkyl group can be split and released, for exampleby treating with a basic agent, for example one of thenucleophilic-reacting bases mentioned further below; a carboxyl groupesterified by a suitable arylmethyl grouping can be split and released,for example by radiation, preferably with ultra-violet light, forexample of less than 290 mμ when the arylmethyl group is, for example, abenzyl radical optionally substituted in the 3-, 4- and/or 5-position,for example by lower alkoxy and/or nitro groups, or with longer-waveultraviolet light, for example of above 290 mμ, when the arylmethylgroup is, for example, a benzyl radical substituted in the 2-position bya nitro group; a carboxyl group esterified by a suitably substitutedmethyl group, such as tert.-butyl or di-phenylmethyl, can be split andreleased, for example, by treating with a suitable acid agent, such asformic acid or trifluoroacetic acid, optionally with the addition of anucleophilic compound, such as phenol or anisole; and an esterifiedcarboxyl group that can be split by hydrogenolysis, for examplebenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, can be split and releasedby hydrogenolysis, for example by treating with hydrogen in the presenceof a noblemetal, for example a palladium, catalyst. In addition, acarboxyl group esterified with a lower alkenyl group, such as with2-lower alkenyl, especially allyl, can be converted oxidatively, forexample by treating with ozone, followed by a reducing agent, forexample dimethyl sulphide, into a formylmethoxycarbonyl group, fromwhich the carboxyl group can be released by treating with a base, suchas a secondary amine, for example dimethylamine; or a 2-loweralkenyloxycarbonyl group, for example allyloxycarbonyl, can beisomerised, for example by treating with tristriphenylohosphine rhodiumchloride, palladium-on-carbon, or an alkali metal-lower alkanolate, forexample potassium tert.-butylate, in dimethyl sulphoxide to form a1-lower alkenyloxycarbonyl group and this can be split hydrolyticallyunder weakly acidic or weakly basic conditions. A 2-oxoethoxycarbonyl or2-cyanoethoxycarbonyl group optionally substituted in the 2-position bylower alkyl or by aryl, for example the acetonyloxycarbonyl or2-cyanoethoxycarbonyl group, can be converted under mild conditions,that is at room temperature or while cooling, by treatment with asuitable base, into the corresponding salt of this carboxyl group, fromwhich the free carboxyl group can be obtained by acidification. Suitablebases are nucleophilic-reacting metal, such as alkaline earth metal, andespecially alkali metal, bases, such as corresponding hydroxides,carbonates, bicarbonates, alkoxides, phenolates, mercaptides,thiophenolates or amides, for example sodium hydroxide, sodiumcarbonate, sodium bicarbonate, sodium ethanolate, sodium thiophenolate,sodium amide or sodium morpholide, or corresponding lithium or potassiumcompounds, which are used in water or in aqueous or hydroxylgroup-containing or alternatively polar inert solvents with subsequenttreatment with water. To split the 2-cyanoethoxycarbonyl groups, it isalso possible to use tertiary amines, such as tri-lower alkylamine, forexample triethylamine or Hunig base, or cyclic or bicyclic amines orimines such as N-methylmorpholine or 1,5-diazabicyclo[5,4,0]undec-5-ene,in an inert solvent, such as methylene chloride or tetrahydrofuran,wherein the corresponding ammonium salts of the carboxyl compound areobtained directly A substituted silylet hoxycarbonyl group can beconverted into the free carboxyl group by treatment with a salt ofhydrofluoric acid that yields fluoride anions, such as an alkali metalfluoride, for example sodium or potassium fluoride, in the presence of amacrocyclic polyether ("crown ether"), or with a fluoride of an organicquaternary base such as tetraalkylammonium fluoride ortrialkylarylammonium fluoride, for example tetraethylammonium fluorideor tetrabutylammonium fluoride, in the presence of an aprotic polarsolvent, such as dimethyl sulphoxide or N,N-dimethylacetamide. Apentachlorophenoxycarbonyl group can be converted into a free carboxylgroup under mild conditions, for example by dilute sodium carbonatesolution or sodium bicarbonate solution or by an organic base in thepresence of water.

A carboxyl group protected, for example, by silylation or stannylation,can be released in the usual manner by solvolysis, for example bytreating with water or an alcohol.

If there is more than one protected carbcxyl group present in a compoundobtainable in accordance with the invention these may be converted intofree carboxyl groups either jointly or selectively.

In a compound of the formula I obtainable in accordance with the processthat contains a free carboxyl group, such a group can be converted in amanner known per se into a protected carboxyl group. For example, estersare obtained, for example, by treating with a suitable diazo compound,such as a diazo-lower alkane, for example diazomethane or diazobutane,or a phenyldiazo-lower alkane, for example diphenyldiazomethane, ifnecessary in the presence of a Lewis acid, such as, for example, borontrifluoride, or by reacting with an alcohol suitable for esterificationin the presence of an esterifying agent, such as a carbodiimide, forexample dicyclohexylcarbodiimide, or carbonyldiimidazole, or furtherwith an N,N'-disbustituted O- or S-substituted isourea or isothiourea,in which an O- and S-substituent is, for example, lower alkyl,especially tert.-butyl, phenyl-lower alkyl or cycloalkyl, and N- orN'-substituents are, for example, lower alkyl, especially isopropyl,cycloalkyl or phenyl, or according to any other known and suitablemethod of esterification, such as reacting a salt, optionally producedin situ, of the acid with a reactive ester of an alcohol and a stronginorganic acid or strong organic sulphonic acid. Further, acid halides,such as acid chlorides (produced, for example, by treating with oxalylchloride), activated esters (formed, for example, with N-hydroxynitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides(obtained, for example, with haloformic acid lower alkyl esters, such aschloroformic acid ethyl ester or chloroformic acid isobutyl ester, orwith haloacetic acid halides, such as trichloroacetic acid chloride) canbe converted into an esterified carboxyl group by reacting withalcohols, optionally in the presence of a base, such as pyridine.

In a compound of the formula I having an esterified carboxyl group, thisgroup can be converted into a different esterified carboxyl group, forexample 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl can be convertedinto 2-iodoethopxycarbonyl by treating with an iodine salt, such assodium iodide, in the presence of a suitable solvent, such as acetone.

In a compound having a free carboxyl group obtainable according to theprocess, such a group can also be converted into an optionallysubstituted hydrazinocarbonyl group, by reacting preferably reactivefunctionally modified derivatives, such as the above-mentioned activatedesters, or mixed anhydrides of the corresponding acid with hydrazines.

A carboxyl group protected by an organic silyl or stannyl group can beformed in a manner known per se, for example by treating the compoundcontaining carboxyl or a salt thereof, such as an alkali metal salt, forexample a sodium salt, thereof, with a suitable silylation orstannylation agent.

In the process according to the invention, and in additional steps to becarried out where applicable or where necessary, if required freefunctional groups that do not participate in the reaction aretransiently protected in a manner known per se: for example, free aminogroups are transiently protected, for example, by acylation, tritylationor silylation; free hydroxy and. mercapto groups, for example byetherification or esterification, inclusive of silylation; and can, ifdesired, be released individually or jointly in a manner known per seafter the reaction. For example amino, hydroxy, mercapto, carboxyl orsulpho groups present in a starting material may be protected, forexample in the form of acylamino groups, such as those mentioned above,for example the 2,2,2-trichloroethoxycarbonylamino group,2-bromoethoxycarbonylamino group, 4-methoxybenzyloxycarbonylamino groupor tert.-butoxycarbonylamino group, or in the form of aryl- oraryl-lower alkylthioamino groups, for example the2-nitro-phenylthioamino group or arylsulphonylamino group, for examplethe 4-methylphenylsulphonylamino group, in the form of 1-loweralkoxycarbonyl-2-propylideneamino groups or of theo-nitrophenoxyacetylamino groups, or of acyloxy groups, such as thosementioned above, for example the tert.-butoxycarbonyloxy group,2,2,2trichloroethoxycarbonyloxy group, 2 -bromoethoxycarbonyloxy groupor p-hitrobenzyloxycarbonyloxy group, or corresponding acylthio groups,or in the form of esterified carboxy groups, such as those mentionedabove, for example the tert.-butoxycarbonyloxy group,2,2,2-trichloroethoxycarbonyl group, 2-bromoethoxycarbonyloxy group orp-nitrobenzyloxycarbonyloxy group, or corresponding acylthio groups, orin the form of esterified carboxy groups, such as those mentioned above,for example the diphenylmethoxycarbonyl group, p-nitrobenzyloxycarbonylgroup, acetonyloxycarbonyl group or 2-cyanoethoxycarbonyl group, or ofsubstituted sulpho groups, such as the above-mentioned lower alkylsulphogroups, for example the methylsulcho group, and when the reaction iscomplete may be released, where applicable after converting theprotective group. For example, a 2,2,2-trichloroethoxycarbonylaminogroup or 2-iodoethoxycarbonylamino group or alternatively ap-nitrobenzyloxycarbonylamino group may be split by treating withsuitable reducing agents, such as zinc in the presence of aqueous aceticacid or hydrogen in the presence of a palladium catalyst adiphenylmethoxycarbonylamino group or tert.-butylcarbonylamino group maybe split by treating with formic acid or trifluoroacetic acid: an aryl-or aryl-lower alkylthioamino group may be split by treating with anucleophilic reagent such as sulphurouse acid; an arylsulphonylaminogroup may be split by means of electrolytic reduction; a 1-loweralkoxycarbonyl-2-propylideneamino group by treating with aqueous mineralacid, and a tert.-butoxycarbonyloxy group by treating with formic ortrifluoroacetic acid or a 2,2,2-trichloroethoxycarbonyloxy group orp-nitrobenzyloxycarbonyloxy group may be split by treating with achemical reducing agent, such as zinc in the presence of aqueous aceticacid, or with hydrogen in the presence of a palladium catalyst; and adiphenylmethoxycarbonyl group may be split by treating with formic ortrifluoroacetic acid or by hydrogenolysis: an acetonyloxy- orcyanoethoxycarbonyl group may be split by treating with bases, such assodium bicarbonate or 1,5-diazabicyclo[5,4,0]undec-5-ene, and asubstituted sulpho group by treating with an alkali metal halide; thesplitting may, if desired, in each case be carried out in stages.

Furthermore, in a resulting compound functional substituents, such asfree amino, hydroxy, mercapto, carboxy or sul-oho groups, may befunctionally modified by processes known per se, for example byalkylation, acylation or esterification or substitution.

Thus, an amino, hydroxy, mercapto, carboxy or sulpho group may bealkylated, for example methylated, by treating with an alkylatingreagent, such as a diazo compound, for example diazomethane, or with areactive ester of an alcohol, for example dimethyl sulphate, or amino,hydroxy or mercapto groups may be acylated, for example, acetylated, bytreating with a reactive functional derivative of an acid, for examplean anhydride or acid chloride, such as acetic anhydride or acetylchloride. Further, for example an amino group may be converted into asulphoamino group by treating with sulphur trioxide, preferably in theform of a complex with an organic base such as a tri-lower alkylamine,for example triethylamine.

A hydroxy group in the substituent R_(a), especially the hydroxy groupin a 1-hydroxy-lower alkyl radical, may be converted into ahydroxysulphonyloxy group present in corresponding salt form by treatingwith a sulphur trioxide complex, for example the complex with dioxan orwith a tertiary nitrogen base, such as tri-lower alkylamine, for exampletriethylamine, N,N-di-lower alkylaniline, for example, N,Ndimethylaniline, or especially with pyridine, or alternatively bytreating with the amidosulphonic acid, optionally in the presence ofpyridine, and the hydroxysulphonyloxy group in salt form can beconverted into a hydroxysulphonyloxy group present in metal salt form bydouble reaction with a corresponding metal hydroxide, metal carbonate,or metal bicarbonate, such as an alkali metal, for example sodium,hydroxide, carbonate or bicarbonate.

In compounds obtainable according to the invention, in a manner knownper se, primary and secondary hydroxy groups may also be converted intoaldehyde or keto groups by oxidation, for example according toPfitzner-Moffatt, or, if necessary after acylation, may be split offtogether with an adjacent removable hydrogen atom to form a C--C doublebond. Aldehyde or keto groups may be converted into hydroxy groups byreduction, for example with complex metal hydrides, or into acetals orketals by treating with alcohols, into the corresponding imines, oximesor hydrazones by treating with an amine, hydroxylamine or hydrazine, orinto the corresponding methylidene compounds by treating with a Wittigreagent. Resulting acetals or ketals may be converted into thecorresponding aldehydes or ketones, for example by treating withtrimethyliodosilane. In compounds obtained according to the invention,furthermore, in a manner known per se, C--C double bonds may be reduced,for example with catalytically activated hydrogen. Halogen, such asbromine or iodine, substituents may be replaced by hydrogen by treating,for example, with zinc/silver in methanol or methanol/acetic acid, ormay be converted into 1-substituted 1-hydroxymethyl groups, for examplethe 1-hydroxyethyl group, by treating with an organometal compound, suchas methyl magnesium bromide or butyl lithium, followed by an aldehyde,for example acetaldehyde. A nitro or azido group may be converted intoan amino group, for example by treating with catalytically activated,for example by a palladium or platinum oxide catalyst, hydrogen. Thementioned subsequent reactions can be carried out both at theappropriate places in the radicals R_(a) and in the radicals R₁.

Salts of compounds of the formula I may be produced in a manner knownper se. For example, salts of such compounds with acid groups can beformed for example by treating with metal compounds such as alkali metalsalts of suitable carboxylic acids, for example the sodium salt ofα-ethylcaproic acid, or with ammonia or a suitable organic amine,wherein preferably stoichiometric amounts or only a small excess of thesalt-forming agent is used. Salts of carboxylic acids of the formula Imay also be obtained by splitting under basic conditions the mentionedesters of such compounds that can be split under such conditions, forexample 2-cyanoethyl or acetonyl esters. Acid addition salts ofcompounds of the formula I with basic groupings are obtained in theusual manner, for example by treating with an acid or a suitable anionexchange reagent. Inner salts of compounds of the formula I thatcontain, for example, a salt-forming amino group and a free carboxylgroup may be formed, for example, by neutralising salts such as acidaddition salts to the isoelectric point, for example with weak bases, orby treating with liquid ion exchangers. Salts of 1-oxides of compoundsof the formula I with salt-forming groups may be produced in ananalogous manner.

Salts may be converted in the usual manner into the free compounds:metal and ammonium salts, for example, by treating with suitable acids,and acid addition salts, for example, by treating with a suitable basicagent.

Mixtures of isomers obtained may be separated into the individualisomers by methods known per se: mixtures of diastereoisomeric isomers,for example, by fractional crystallisation, adsorption chromatography(column or thin-layer chromatography) or other suitable separatingprocesses. Resulting racemic compounds can be separated into theantipodes in the usual manner, optionally after introducing suitablesalt-forming groupings, for example by forming a mixture ofdiastereoisomeric salts and converting the optically active salts intothe free compounds, or by fractional crystallisation from opticallyactive solvents.

In all subsequent conversions of the compounds obtained, the reactionsthat are preferred are those carried out under neutral, alkaline orweakly basic conditions.

The process also includes those embodiments according to which compoundsproduced as intermediates are used as starting substances and theremaining process steps are carried out with these, or according towhich the process is interrupted at any stage; furthermore, startingsubstances may be used in the form of derivatives or may be formed insitu, optionally under the conditions of the reaction. For example, astarting material of the formula II in which Z is oxygen may be producedin situ from a compound of the formula II in which Z is an optionallysubstituted methylidene group, by ozonisation and subsequent reductionof the ozonide formed, analogously to the method given in stage 2.5,whereupon, especially when R₁ is hydrogen, the cyclisation to thecompound of the formula I takes place in the reaction solution.

The starting compounds of the formula II and the preliminary stages maybe produced, for example, according to the following reaction schemes 1,2 and 3. ##STR8##

In the compounds of the formulae IV, V, VI and II in the reaction schemeI and in the compounds of the formulae Xa, XI, XII and IVa in thereaction scheme 2, Z' is oxygen, sulphur or alternatively, especiallywhen R₁ is hydrogen, a methylidene group optionally substituted by onoor two substituents Y, which group can be converted by oxidation into anoxo group Z. A substituent Y of this methylidene group is an organicradical, for example one of the organic radicals mentioned under R₁,such as one of the mentioned, optionally substituted, lower alkyl,cycloalkyl, cycloalkyl-lower alkyl, phenyl or phenyl-lower alkylradicals, and especially one of the functionally modified, such asesterified, carboxyl groups. Esterification with an optically activealcohol such as 1-menthol is included. This methylidene group preferablycarries one of the substituents mentioned. Themethoxycarbonylmethylidene and the (1)-menthyloxycarbonylmethylidenegroup Z' are given special mention. The latter can be used for theproduction of optically active compounds of the formulae IV to VI andII.

Stage 1.1

A thioazetidinone of the formula IV is obtained by treating a4-W-azetidinone of the formula III, in which W represents a nucleofugeleaving group with a mercapto compound R₁ --C(═Z')--SH or with a salt,for example an alkali metal salt such as a sodium or potassium saltthereof, and, if desired, separating an isomeric mixture obtained intothe individual isomers, and/or if desired converting a group R_(a) or R₁in a compound obtained into a different group R_(a) or L R₁respectively, and/or, if desired, converting an optionally substitutedmethylidene group Z' into an oxo group Z.

The nucleofuge leaving group W in a starting material of the formula IIIis a radical that can be replaced by the nucleophilic radical R₁--C(═Z')--S--. Such groups W are, for example, acyloxy radicals,sulphonyl radicals R_(o) --SO₂ --, in which R_(o) is an organic radical,azido or halogen. In an acyloxy radical W, acyl is the radical or anorganic carboxylic acid, including an optically active carboxylic acid,and has, for example, the same meaning as the acyl radical R₁ --CO--, inwhich R₁ is hydrogen or one of the mentioned organic radicals bonded bya carbon atom, for example, one of the mentioned, optionally substitutedlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl or phenyl-loweralkyl radicals. In a sulphonyl radical R_(o) --SO₂ --, R_(o) is, forexample, an optionally substituted aliphatic, araliphatic or aromatichydrocarbon radical having up to 12 carbon atoms, and is especiallylower alkyl, such as methyl, ethyl or a methyl substituted by anoptically active radical, such as camphoryl, or benzyl, phenyl ortoluyl. A halogen radical W is bromine, iodine or especially chlorine. Wis preferably acetoxy or chlorine.

The nucleophilic substitution may be carried out under neutral or weaklybasic conditions in the presence of water and optionally awater-miscible organic solvent. The basic conditions may be established,for example, by the addition of an inorganic base such as an alkalimetal or an alkaline earth metal hydroxide, carbonate or bicarbonate,for example sodium, potassium or calcium hydroxide, carbonate orbicarbonate. The organic solvents that may be used are, for example,water-miscible alcohols, for example, lower alkanols such as methanol orethanol; ketones, for example lower alkanones such as acetone; amides,for example lower alkanecarboxylic acid amides such asdimethylformamide, and the like. The reaction is usually carried out atroom temperature but can be carried out at elevated or reducedtemperature. The reaction can be accelerated by adding a salt ofhydriodic acid or thiocyanic acid, for example an alkali metal salt,such as a sodium salt.

Both optically inactive cis- or trans-compounds of the formula III andmixtures thereof, or corresponding optically active compounds, can beused in the reaction The group R₁ --C(═Z')--S-- which is introduced isdirected by the group R_(a) especially into the trans-position,irrespective of whether W is in the cis- or trans- position with respectto the R_(a) group. Although predominantly the trans-isomers are formed,occasionally also cis-isomers are isolated. The separation of the cis-and trans-isomers is carried out according to conventional methods,especially by chromatography and/or by crystallisation.

The subsequent ozonisation of a methylidene group Z' can be carried outas described further below. A resulting racemate of the formula IV canbe separated into the optically active compounds.

The compounds of the formula IV are new.

The optically active compounds of the formula IVa covered by the formulaIV can also be produced according to the reaction scheme 2 given below

Azetidinones of the formula III, in which R_(a) is methyl and W isacetyl, phenylsulphonyl or camphor-10-sulphonyl, are known (GermanOffenlegungsschrift No. 1 906 401 or K. Clauss et. al., Liebigs Ann.Chem. 974, 539-560). The remaining compounds of the formula III are new.They can be produced according to methods that are known per se.

The azetidinones of the formula III are produced, for example, by theaddition of chlorosulphonyl isocyanate to correspondingly substitutedvinyl esters and subsequently splitting off the chlorosulphonyl group.In this synthesis, usually mixtures of cis- and trans-isomers areobtained, which if desired can be separated into the pure cis- ortrans-isomers, for example by chromatography and/or crystallisation ordistillation. The pure cis- and trans-isomers are present in the form ofracemic compounds and can be separated into their optical antipodes, forexample when the acyl in the acyloxy radical W in compounds of theformula III stems from an optically active acid The optically activecompounds of the formula IIIa covered by the formula III can be producedaccording to reaction scheme 3 given below.

Stage 1.2

An α-hydroxycarboxylic acid compound of the formula V is obtained byreacting a compound of the formula IV with a glyoxylic acid compound ofthe formula OHC--C(═C)--R₂ ^(A) or a suitable derivative such as ahydrate, hemihydrate or semiacetal, for example a semiacetal with alower alkanol, for example, methanol or ethanol, and, if desired,separating a so obtained isomeric mixture into the individual isomers,and/or, if desired, converting a group R_(a) or R₁ in a compoundobtained into a different group R_(a) or R₁ respectively, and/or, ifdesired, converting an optionally substituted methylidene group Z' intoan oxo group Z.

The compound V is usually obtained as a mixture of the two isomers (withreference to the grouping ##STR9## It is possible, however, also toisolate the pure isomers therefrom.

The addition reaction of the glyoxylic acid ester compound to thenitrogen atom of the lactam ring takes place at room temperature or, ifnecessary, while heating, for example up to approximately 100° C., andin the absence of an actual condensation agent and/or without theformation of a salt. When using the hydrate of the glyoxylic acidcompound, water is formed which, if necessary, is removed bydistillation, for example azeotropically, or by using a suitabledehydration means such as a molecular sieve. Preferably the process iscarried out in the presence of a suitable solvent, such as, for example,dioxan, toluene or dimethylformamide, or of a solvent mixture, ifdesired or necessary in an inert gas atmosphere, such as a nitrogenatmosphere.

Both pure optically inactive cis- or trans-compounds of the formula TVand mixtures thereof, or corresponding optically active compounds, canbe used in the reaction. A racemic compound of the formula V obtainedcan be separated into the optically active compounds.

Stage 1.3

Compounds of the formula VI, in which X_(o) represents a reactiveesterified hydroxy group, especially halogen or organic sulphonyloxy,are produced by converting the secondary hydroxy group in a compound ofthe formula V into a reactive esterified hydroxy group, especially intohalogen, for example chlorine or bromine, or into an organicsulphonyloxy group such as lower alkylsulphonyloxy, for examplemethylsulphonyloxy, or arylsulphonyloxy, for example4-methylphenylsulohonyloxy, if desired separating an isomeric mixtureobtained into the individual isomers, and, if desired, converting agroup R_(a) or R₁ in a compound obtained into a different group R_(a) orR₁ respectively, and/or, if desired, converting an optionallysubstituted methylidene group Z' into an oxo group Z.

The compound VI may be obtained in the form of mixtures of the isomers(with reference to the grouping ##STR10## or in the form of pureisomers.

The above reaction is carried out by treating with a suitableesterifying agent, using, for example, a halogenating agent such as athionyl halide, for example the chloride, a phosphorus oxyhalide,especially the chloride, or a halophosphonium halide such astriphenylphosphine dibromide or diiodide, and a suitable organicsulphonic acid halide such basic, especially an organic basic, agentsuch as an aliphatic tertiary amine, for example triethylamine,diisopropylethylamine or "polystyrene-Hunig base", or a heterocyclicbase of the pyridine type, for example pyridine or collidine. Preferablythe reaction is carried out in the presence of a suitable solvent, forexample dioxane or tetrahydrofuran, or of a solvent mixture, ifnecessary while cooling and/or in an inert gas atmosphere, such as anitrogen atmosphere.

In a compound of the formula VI obtainable in this manner, a reactiveesterified hydroxy group X_(o) can be converted into a differentreactive esterified hydroxy group in a manner known per se. For example,a chlorine atom can be exchanged for a bromine or iodine atom bytreating the corresponding chlorine compound with a suitable bromine oriodine reagent, especially with an inorganic bromide or iodide salt suchas lithium bromide., preferably in the presence of a suitable solventsuch as ether.

Both pure optically inactive cis- or trans-compounds of the formula Vand mixtures thereof, or corresponding optically active compounds, canbe used in the reaction. A racemic compound of the formula VI obtainedcan be separated into the optically active compounds.

Stage 1.4

A starting material of the formula II is obtained by treating a compoundof the formula VI in which S_(o) represents a reactive esterifiedhydroxy group, with a suitable phosphine compound such as a tri-loweralkylphosphine, for example tri-n-butylphosphine, or atriaryl-phosphine, for example triphenylphosphine, or with a suitablephosphite compound such as a tri-lower alkyl phosphite, for exampletriethyl phosphite, or an alkali metal dimethyl phosphite, whereindepending on the choice of reagent a compound of the formula IIA or IIBcan be obtained, and if desired converting a group R_(a) or R₁ in acompound obtained into a different group R_(a) or R₁ respectively,and/or if desired converting an optionally substituted methylidene groupZ' into an oxo group Z.

The above reaction is preferably carried out in the presence of asuitable inert solvent such as a hydrocarbon, for example hexane,cyclohexane, benzene, toluene or xylene; or an ether, for exampledioxan, tetrahydrofuran or diethylene glycol dimethyl ether, or of asolvent mixture. Depending on the reactivity, the operation is carriedout while cooling or at elevated temperature, approximately between -10°+100°, preferably at approximately 20° to 80°, and/or in an inert gasatmosphere, such as a nitrogen atmosphere. In order to prevent oxidativeprocesses, catalytic amounts of an antioxidant, for examplehydroquinone, may be added.

When using a phosphine compound the reaction is usually carried out inthe presence of a basic agent, such as an organic base, for example anamine, such as triethylamine, diisopropylethylamine or"polystyrene-Hunig base", and thus the phosphoranylidene startingmaterial of the formula IIA, which is formed from the correspondingphosphonium salt, is obtained directly.

Both pure optically inactive cis- or trans-compounds of the formula VIand mixtures thereof, be used in the reaction. A racemic compound of theformula II obtained can be separated into the optically activecompounds.

In the compounds of the formulae II to VI R_(a) preferably representsone of the mentioned organic radicals bonded by a carbon atom to thering carbon atom, or alternatively an etherified hydroxy group, in whichfunctional groups optionally present in such a radical R_(a) arepreferably in protected form.

The separation of the above-mentioned cis- trans compounds into the purecis- and trans-isomers is effected according to customary separationmethods, for example by chromatography and/or by distillation orcrystallisation.

The above-mentioned racemic compounds are split into their opticalantipodes by methods known per se.

One of these methods consists in reacting a racemic compound with anoptically active auxiliary, separating the resulting mixture of twodiastereoisomeric compounds by means of suitable physical/chemicalmethods and then splitting the individual diastereoisomeric compoundsinto the optically active compounds.

Particularly suitable racemic compounds for separating into antipodesare those that possess an acidic group, for example racemic compounds ofthe compounds of the formula I. Others of the described racemiccompounds can be converted into acidic racemic compounds by simplereactions. For example, racemic compounds carrying aldehyde or ketogroups react with a hydrazine derivative carrying acid groups, forexample 4-(4-carboxyphenyl)-semicarbazide to form the correspondinghydrazone derivatives, or compounds containing alcohol groups react witha dicarboxylic acid anhydride, for example phthalic acid anhydride, toform the racemic compound of an acidic semiester.

These acidic racemic compounds may be reacted with optically activebases, for example esters of optically active amino acids, or(-)-brucine, (+)-quinidine, (-)-quinine, (+)-cinchonine,(+)-dehydroabietylamine, (+)- and (-)-ephedrine, (+)- and(-)-1-phenylethylamine or their N-mono- or N,N-dialkylated derivatives,to form mixtures consisting of two diastereoisomeric salts.

In racemic compounds containing carboxyl groups, for example in racemiccompounds that contain a functionally modified carboxymethylidene groupZ', this carboxyl group may already be esterified by, or esterificationmay be carried out by, an optically active alcohol such as (-)-menthol,(+)-borneol, (+)- or (-)-2-octanol, whereupon after subsequent isolationof the desired diastereoisomer, the carboxyl group is released, or thepart of the molecule containing the esterified carboxyl group, forexample the esterified carboxymethylidene radical, is split off.

Racemic compounds containing hydroxy groups may likewise be split intotheir optical antipodes, for which especially optically active acids ortheir reactive functional derivatives that form diastereoisomeric esterswith the said alcohols are used. Such acids are, for example (-)-abieticacid, D(+)- and L(-)-malic acid, N-acylated optically active aminoacids, (+)- and (-)-camphanic acid, (+)- and (-)-ketopinic acid,L(+)-ascorbic acid, (+)-camphoric acid, (+)-camphor-10-sulphonicacid(β), (+)- or (-)-α-bromocamphor-π-sulphonic acid, D(-)-quinic acid,D(-)-isoascorbic acid, D(-)- and L(+)-mandelic acid,(+)-1-menthoxyacetic acid, D(-)- and L(+)-tartaric acid and theirdi-O-benzoyl- and di-O-p-toluyl derivatives. The acyl radicals of theoptically active acids mentioned may be present, for example, as acyl incompounds of the formula III or as R₁ --C(═O)-- in compounds of theformulae II and IV to VI, and render possible the splitting of theracemates of such compounds. If desired or necessary, when the splittingof the racemic compound is complete the optically active group R₁--C(═O)-- can be converted into a desired optically inactive group R₁--C(═O)--.

Racemic compounds containing hydroxy groups may be converted into amixture of diastereoisomeric urethanes, for example by reacting withoptically active isocyanates, such as with (+)- or (-)-1-phenylethylisocyanate.

Basic racemic compounds can form diastereoisomeric salts with theoptically active acids. Racemic compounds containing double bonds may beconverted, for example by platinum chloride and(+)-1-phenyl-2-aminopropane, into mixtures of diastereoisomeric complexsalts.

Physical/chemical methods, especially fractional crystallisation, aresuitable for separating the diastereoisomeric mixtures. It is alsopossible, however, to use chromatographic methods, above allsolid-liquid chromatography. Readily volatile diastereoisomeric mixturesmay also by separated by distillation or gas chromatography.

Splitting the separated diastereoisomers into the optically activestarting materials is likewise carried out according to customarymethods. The acids or the bases are freed from the salts, for example bytreating with stronger acids or bases respectively than those originallyused. The desired optically active compounds are obtained from theesters and urethanes, for example by alkaline hydrolysis or by reductionwith a complex hydride such as lithium aluminium hydride.

A further method of separating the racemic compounds consists in thechromatography on optically active absorption layers, for example oncane sugar.

According to a third method, the racemic compounds can be dissolved inoptically active solvents and the more sparingly soluble opticalantipode is crystallised out.

In a fourth method the different reactivity of the optical antipodes incomparison with the biological material, such as microorganisms orisolated enzymes, is used.

According to a fifth method, the racemic compounds are dissolved and oneof the optical antipodes is crystallised out by injecting a small amountof an optically active product obtained according to the above methods.

Optically active trans-compounds of the formula IVa that can be usedaccording to the invention may also be produced in accordance with thefollowing reaction scheme: ##STR11##

Stage 2.1

An oxide of a penicillanic acid compound of the formula VIII is obtainedby oxidizing a penicillanic acid compound of the formula VII in the1-position and if desired converting an R_(a) group in a resultingcompound into a different R_(a) group. The oxidation is carried out in amanner known per se with suitable oxidising agents, such as hydrogenperoxide or inorganic or organic peracids. Suitable inorganic peracidsare, for example, periodic or persulphuric acid. Suitable organicperacids are, for example, percarboxylic acids, such as performic acid,peracetic acid, trifluoroperacetic acid, permaleic acid, perbenzoicacid, 3-chloroperbenzoic acid or monoperphthalic acid, or persulphonicacids, for example p-toluenepersulphonic acid. The peracids may also beproduced in situ from hydrogen peroxide and the corresponding acids. Theoxidation is carried out under mild conditions, for example attemperatures of approximately -50° to approximately +100°, preferably atapproximately -10° to approximately +40°, in an inert solvent.

Racemic 1-oxides of the formula VIII, in which R_(a) is phenoxy ormethoxy, and R₂ ^(A) is methoxy, are known [A. K. Bose et al.,Tetrahedron 28, 5977 (1972)]. The optically active compounds of theformula VIII are new and are also part of the present invention.

Starting compounds of the formula VII are known or can be producedaccording to known processes. For example, they may be obtainedaccording to D. Hauser and H. P. Sigg, Helv. Chimica Acta 50, 1327(1967), by reacting a 6-diazopenicillanic acid ester, which isoptionally produced in situ from a 6-amino-penicillanic acid ester andnitrous acid, with water or an alcohol or an acid of the formulaH-R_(a). Compounds of the formula VII, in which R_(a) is an acyloxygroup, may likewise be obtained according to D. Hauser, by pyrolysing acorresponding 6α- or 6β-N-nitrosoacylaminopenicillanic acid ester in aninert solvent. Compounds of the formula VII, in which R_(a) is hydroxy,have also been described by J. C. Sheehan et al., J. Org. Chem. 39, 1444(1974) (manufacture from the corresponding 6-diazopenicillanic acidcompounds). Further starting materials of the formula VII, in whichR_(a) is optionally protected 1-hydroxyethyl, bromine or iodine, aredescribed by DiNinno et al. (J. Org. Chem. 42 (1967), 2960). In aresulting compound of the formula VIII, an R_(a) group can be convertedinto a different R_(a) group.

Stage 2.2

A 3-methylenebutyric acid compound of the formula IX is obtained bytreating a 1-oxide of a penicillanic acid compound of the formula VIIIwith a mercapto compound R^(o) --SH, and if desired, converting a groupR_(a) in a resulting compound into a different group R_(a).

In the mercapto compound R^(o) --SH and in the reaction product of theformula IX, R^(o) is an optionally substituted aromatic heterocyclicradical having up to 15, preferably up to 9, carbon atoms, and at leastone ring nitrogen atom, and optionally a further ring hetero atom, suchas oxygen or sulphur, which radical is bonded to the thio group --S-- byone of its ring carbon atoms that is bonded to a ring nitrogen atom by adouble bond. Radicals of this type are monocyclic or bicyclic and may besubstituted, for example by lower alkyl, such as methyl or ethyl, loweralkoxy, such as methoxy or ethoxy, halogen, such as fluorine or chlorineor aryl, such as phenyl.

Radicals R^(o) of this type are, for example, monocyclic five-memberedthiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclicradicals of aromatic character, especially monocyclic five-membereddiazacyclic, oxazacyclic and thiazacyclic radicals of aromaticcharacter, and/or especially the corresponding benzdiazacyclic,benzoxazacyclic or benzthiazacyclic radicals, in which the heterocyclicpart is five-membered and has an aromatic character, wherein in R^(o)radicals a substitutable ring nitrogen atom may be substituted, forexample, by lower alkyl. Representative of such R^(o) groups are1-methylimidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl,1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl,1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methylbenzimidazol-2-yl,benzoxazol-2-yl and especially benzthiazol-2-yl.

The reaction is carried out in an inert solvent, such as an aliphatic oraromatic hydrocarbon, for example benzene or toluene, while warming upto the reflux temperature of the solvent used.

Stage 2.3

A 3-methylcrotonic acid compound of the formula X is obtained byisomerising a 3-methylenebutyric acid compound of the formula IX bytreating with a suitable basic agent and, if desired, converting a groupR_(a) in a resulting compound into a different group R_(a).

Suitable basic agents are, for example, organic nitrogen bases such astertiary amines, for example tri-lower alkylamines such as triethylamineor Hunig base, or inorganic bases, which are used in an inert solvent,such as an optionally halogenated hydrocarbon, for example methylenechloride, at room temperature or optionally slightly reduced or elevatedtemperature.

Stage 2.4

A thio compound of the formula XI is obtained by treating a compound ofthe formula X with a suitable reducing agent and simultaneously orsubsequently reacting with an acylation derivative of an acid of theformula R₁ --C(═Z)--OH, or, when Z' represents a methylidene groupoptionally substituted by Y, reacting with an alkyne of the formula R₁--C.tbd.C--Y, and, if desired, converting a group R_(a) or R₁ in acompound so obtained into a different group R_(a) or R₁ respectively,and/or, if desired, converting an optionally substituted methylidenegroup Z' into an oxo group Z.

Suitable reducing agents are, for example, hydride reducing agents suchas alkali metal borohydrides, for example sodium borohydride, or alsozinc in the presence of a carboxylic acid, for example a carboxylic acidof the formula R₁ --C(═O)--OH. The hydride reducing agents are usuallyused in the presence of suitable solvents, such as dimethylformamide.The hydride reduction is preferably carried out in dimethylformamidewith sodium borohydride at temperatures of approximately --50° toapproximately --10°, preferably at approximately -20°, whereupon at thesame temperature the acylating agent and optionally a tertiary base,such as pyridine, are added. The reduction with zinc and a carboxylicacid is optionally carried out in a solvent, for which the carboxylicacid, if liquid, can itself be used, at temperatures of approximately-10 to approximately +50°, preferably at approximately 0° to roomtemperature. The acylating agent can be added to the reduction mixturefrom the beginning or when reduction is complete and optionally afterevaporating off the carboxylic acid used and/or the solvent. Suitableacylating agents are especially anhydrides of the carboxylic acidsmentioned, such as symmetric anhydrides, for example acetic anhydride,or mixed anhydrides, preferably those with hydrohalic acids, that is thecorresponding carboxylic acid halides, for example the chlorides andbromides, such as acetyl bromide. For example a compound of the formulaX may be converted with zinc in a mixture of acetic acid and aceticanhydride at 0° to approximately 20° into a compound of the formula XI,in which R₁ is methyl. Owing to the reduced risk of racemisation, thezinc/carboxylic acid reduction is preferred. The alkyne can also beadded to the reduction mixture from the beginning or when reduction iscomplete. The addition of the 4-mercaptoazetidin-2-one, produced as anintermediate in the reduction, to the triple bond of the alkyne takesplace spontaneously at the reduction temperature.

Stage 2.3a

A thio compound of the formula XI is also obtained by isomerising acompound of the formula Xa in accordance with the reaction conditions ofstage 2.3 by treating with a suitable basic agent, if desired convertinga group R_(a) or R₁ in a compound obtained into different group R_(a) orR₁ respectively, and/or, if desired, converting an optionallysubstituted methylidene group Z' into an oxo group Z.

Stage 2.4a

A compound of the formula Xa is obtained by treating a3-methylenebutyric acid compound of the formula IX in accordance withthe reaction conditions of stage 2.4 with a suitable reducing agent, andsimultaneously or subsequently reacting with an acylating derivative ofa carboxylic acid of the formula R₁ --C(═Z)--OH, or, when Z' representsa methylidene group optionally substituted by Y, with an alkyne of theformula R₁ --C.tbd.C--Y, and, if desired, converting a group R_(a) or R₁in a compound obtained into a different group R_(a) or R₁ respectively,and/or, if desired, converting an optionally substituted methylidenegroup Z' into an oxo group Z.

Stage 2.5

A 2-oxoacetic acid compound of the formula XII is obtained by ozonisinga compound of the formula XI and splitting the ozonide formed to the oxocompound by means of reduction, and if desired converting a group R_(a)or R₁ in a compound obtained into a different group R_(a) or R₁respectively, and/or, if desired, converting an optionally substitutedmethylidene group Z' into an oxo group Z.

The ozonisation is usually carried out with an ozone/oxygen mixture inan inert solvent, such as a lower alkanol, for example methanol orethanol, a lower alkanone, for example acetone, an optionallyhalogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, forexample a halogen-lower alkane, such as methylene chloride or carbontetrachloride, or in a solvent mixture, including an aqueous mixture,preferably while cooling, for example at temperatures of approximately-90° to approximately 0°.

An ozonide obtained as intermediate is, usually without being isolated,split reductively to form a compound of the formula XII, whereincatalytically activated hydrogen, for example hydrogen in the presenceof a heavy metal hydrogenating catalyst, such as a nickel catalyst orpalladium catalyst, preferably on a suitable carrier material, such ascalcium carbonate or carbon, is used; or chemical reducing agents, suchas reducing heavy metals, including heavy metal alloys or amalgams, forexample zinc, in the presence of a hydrogen donor such as an acid, forexample acetic acid, or of an alcohol, for example a lower alkanol, areused; or reducing inorganic salts, such as alkali metal iodides, forexample sodium iodide, or alkali metal bisulphites, for example, sodiumbisulphite, in the presence of a hydrogen donor, such as an acid, forexample acetic acid, or water, are used; or reducing organic compoundssuch as formic acid are used. It is also possible to use as reducingagents compounds that may readily be converted into corresponding epoxycompounds or oxides, wherein the epoxide formation can take place onaccount of a C,C-double bond and the oxide formation on account of anoxide-forming hetero atom, such as a sulphur, phosphorus or nitrogenatom. Compounds of this type are, for example, suitably substitutedethylene compounds (which are converted into ethylene oxide compounds inthe reaction), such as tetracyanoethylene, in particular suitablesulphide compounds (which in the reaction are converted into sulphoxidecompounds), such as di-lower alkyl sulphides, especially dimethylsulphide, suitable organic phosphorus compounds, such as a phosphine,which contains optionally substituted aliphatic or aromatic hydrocarbonradicals as substituents (and which in the reaction is converted into aphosphine oxide), such as tri-lower alkylphosphines, for exampletri-n-butylphosphine, or triarylphosphines, for exampletriphenylphosphine, or phosphites, which contain optionally substitutedaliphatic hydrocarbon radicals as substituents (and in the reaction areconverted into phosphoric acid triesters), such as tri-lower alkylphosphites, usually in the form of corresponding alcohol adductcompounds, such as trimethyl phosphite, or phosphorous acid triamides,which contain optionally substituted aliphatic hydrocarbon radicals assubstituents, such as hexa-lower alkyl phosphorous acid triamides, forexample hexamethyl phosphorous acid triamide, the latter preferably inthe form of a methanol adduct, or suitable nitrogen bases (which in thereaction are converted into the corresponding N-oxides), such asheterocyclic nitrogen bases of aromatic nature, for example bases of thepyridine types and especially pyridine itself. The splitting of theusually unisolated ozonide is normally carried out under the conditionsused for its manufacture, that is to say, in the presence of a suitablesolvent or solvent mixture, and while cooling or heating gently, whereinpreferably temperatures of approximately -10° C. to approximately +25°C. are used and the reaction usually terminates at room temperature.

Stage 2.6

A compound of the formula IVa is obtained by solvolysing a compound ofthe formula XII and, if desired, converting a group R_(a) or R₁ in acompound so obtained into a different group R_(a) or R₁, and/or, ifdesired, converting an optionally substituted methylidene group Z' intoan oxo group Z.

The solvolysis may be carried out by hydrolysis alcoholysis orhydrazinolysis. The hydrolysis is carried out with water, optionally ina water-miscible solvent. The alcoholysis is usually carried out with alower alkanol, for example methanol or ethanol, preferably in thepresence of water and an organic solvent, such as a loweralkanecarboxylic acid lower alkyl ester, for example ethyl acetate,preferably at room temperature, if necessary while cooling or heating.The hydrazinolysis is carried out in a conventional manner with asubstituted hydrazine, for example with phenylhydrazine or anitrophenylhydrazine, such as 2-nitrophenylhydrazine,4-nitro-phenylhydrazine or 2,4-dinitrophenylhydrazine, which ispreferably used in an approximately equimolar amount, in an organicsolvent, such as an ether, for example tetrahydrofuran, dioxan, diethylether, an aromatic hydrocarbon, such as benzene or toluene, ahalogenated hydrocarbon, such as methylene chloride, chlorobenzene ordichlorobenzene, an ester, such as ethyl acetate, or the like, attemperatures between approximately room temperature and approximately65° C. The α-keto. compound of the formula XII does not necessarily haveto be isolated. If, for example, the ozonide is split in the presence ofa solvolysing agent, such as, for example, water, a compound of theformula IVa can be obtained directly.

Optically active cis-, trans- and cis-trans compounds of the formulaIIIa may also be obtained in accordance with the following reactionscheme: ##STR12##

Stage 3.1

A 3-methylenebutyric acid compound of the formula XIII is obtained bytreating a 1-oxide of a penicillanic acid compound of the formula VIIIin the presence of a tri-lower alkyl phosphite with an organiccarboxylic acid acyl-OH, if desired converting a group R_(a) in aresulting compound into a different group R_(a), and/or isolating thecis- and/or the trans-compound from a resulting cis-trans compound.

A suitable tri-lower alkyl phosphite is, for example,trimethylphosphite. A suitable organic carboxylic acid acyl-OH is, forexample, a carboxylic acid R₁ --COOH, in which R₁ represents hydrogen orone of the mentioned organic radicals bonded by a carbon atom, forexample one of the mentioned lower alkyl, cycloalkyl, cycloalkyl-loweralkyl, phenyl or phenyl-lower alkyl radicals. Preferred are loweralkanecarboxylic acids, including formic acid, especially acetic acid.

The reaction is effected, analogously to A. Suarato et. al., TetrahedronLetters, 42, 4059-4062, 1978, in an inert organic solvent, for example ahydrocarbon, such as benzene, toluene or xylene, or an ether-typesolvent, such as dioxan or tetrahydrofuran, or a solvent mixture, atelevated temperature, approximately up to the reflux temperature of thesolvent used, at approximately 50° to 150° C., preferably atapproximately 80° to approximately 100° C.

In the reaction a mixture of the cis- and trans-compounds is obtained.By means of customary separating methods, such as crystallisation orchromatography, the cis- and/or trans- compound can be obtained in pureform.

Stage 3.2

A 3-methylcrotonic acid compound of the formula XIV, in which W'represents acyloxy, is obtained by isomerising a 3-methylenebutyric acidcompound of the formula XIII by treating with a suitable basic agent,and if desired converting a group R_(a) in a resulting compound into adifferent group R_(a), and/or, if desired isolating the cis- and/ortrans-compound from a resulting cis-trans compound.

The basic isomerisation is carried out as described in stage 2.3. Thesubsequent separation into pure compounds, to be carried out if desired,is effected as described in stage 3.1.

Stage 3.3

A compound of the formula XIV, in which W' represents halogen, isobtained by treating a penicillanic acid compound of the formula VIIwith a halogenating agent yielding positive halogen ions and, ifnecessary, treating a possibly resulting intermediate with a base, andif desired converting a group R_(a) in a resulting compound of theformula XIV into a different group R_(a), and/or isolating the cis-and/or the trans-compound from a resulting cis-trans compound.

Halogenating agents that yield positive halogen ions are for exampleelemental halogens, such as chlorine, bromine or iodine; mixed halogens,such as BrCl, ClI or BrI; sulphuryl halides, such as sulphuryl chlorideor sulphuryl bromide; N-haloamides or N-haloimides, such asN-chloroacetamide, N-bromoacetamide, N-chlorosuccinimide,N-bromosuccinimide or N,N'-dibromohydantoine; or organic hypohalites,especially lower alkanoyl hypohalites, such as acetyl hypochlorite,propionyl hypochlorite, butyryl hypochlorite, acetyl hypobromite,propionyl hypcbromite, butyryl hypobromite and the like.

The reaction is carried out analogously to U.S. Pat. No. 3,920,696 orSt. Kukolja, Journ. Am. Chem. Soc. 93, 6267 (1971), in an inert aproticsolvent, especially in a halogenated hydrocarbon, such as methylenechloride or carbon tetrachloride, at temperatures between approximately-80° and approximately +80° C., preferably at approximately -76° C. toapproximately room temperature.

The molar ratio of halogenating agent to compound of the formula VII isbetween 1:1 and 3:1 or even higher. If the molar ratio is approximately1:1, a compound of the formula ##STR13## is obtained as intermediate,which can be converted into a compound of the formula XIV by treatingwith a base, such as a tertiary amine, for example triethylamine. Byusing at least 2 moles of halogenating agent or more per mole ofpenicillanic acid compound, the desired compound of the formula XIV isobtained even without subsequent treatment with a base.

In the ring opening reaction a mixture of the cis- and trans-compound isobtained, the trans-compound preferably being formed. By customaryseparating methods, such as crystallisation or chromatography, the cis-and/or the trans-compounds can be obtained in pure form.

Stage 3.4

A 2-oxoacetic acid compound of the formula XV, in which W' representsacyloxy or halogen, is obtained by ozonising a compound of the formulaXIV and splitting the ozonide formed by reduction to form the oxo group,and, if desired, converting a group R_(a) in a resulting compound into adifferent group R_(a), and/or, if desired, isolating the cis- and/ortrans- compound from a resulting cis-trans compound.

The ozonisation and the reduction of the ozonide formed are carried outas described in stage 2.5. The separation into pure compounds carriedout subsequently if desired, is effected as described in stage 3.1.

Stage 3.5

A compound of the formula IIIa, in which W has the meaning given underformula III, is obtained by solvolysing a compound of the formula XV, inwhich W' represents acyloxy or halogen, and if desired converting agroup R_(a) in a resulting compound into a different group R_(a),and/or, if desired, converting a group W' into a different group W' orW, and/or if desired isomerising a resulting cis-compound to form thecorresponding trans-compound, and/or isolating the cis- and/ortrans-compound from a resulting cis-trans compound.

The solvolysis is carried out as described in stage 2.6. When W ishalogen, hydrazinolysis is preferably used. In this case too it is notnecessary to isolate the intermediate of the formula XV after theozonisation and reduction reaction, but it can be produced in situ andsolvolysed directly.

In a resulting compound of the formula IIIa in which W representsacyloxy or halogen, this group can be converted into a different group Wby nucleophilic exchange, wherein the group W being introduced must bemore nucleophilic than that leaving. This exchange may be carried outanalogously to stage 1.1, for example, by treating with an alkali metalsalt, such as a sodium or potassium salt of an acid H-W.

In this exchange of W for a different W, and in the subsequent exchangefor a group R₁ --C(═Z')--S-- according to stage 1.1, the opticallyactive trans-compounds of the formula IIIa and IVa respectively areobtained in excess, irrespective of whether a cis- or trans-compound wasused as starting material.

By isomerisation, for example by treating with a mild Lewis acid incatalytic amounts, a resulting cis-compound can be converted into atrans-compound. The isomerisation with a Lewis acid is carried out in aninert solvent at elevated temperature, approximately at 50° to 150° C.,for example under reflux in benzene.

In the compounds II, IV to XV, IIIa and IVa, a group R_(a), R₁ or R₂^(A) can be converted according to methods known per se into a differentR_(a), R₁ or R₂ ^(A) group respectively, wherein, taking intoconsideration the various functional groups, it is possible to use thesame methods as are given for converting these substituents in thecompounds of the formula I.

In the compounds IV (including IVa) to VI and II, an optionallysubstituted methylidene group Z' may be converted into an oxo group Z byozonisation and subsequent reduction of the ozonide formed, according tothe process described in stage 2.5.

The invention likewise includes the new intermediates, such as those ofthe formulae IIIa and IV (including IVa) to XV and especially of theformula II, and the processes for their production.

The pharmacologically acceptable compounds of the invention may be used,for example, for the production of pharmaceutical preparations thatcontain an effective amount of the active substance together or inadmixture with inorganic or organic, solid or liquid, pharmaceuticallyacceptable carriers that are suitable for enteral or parenteraladministration. For example, tablets or gelatin capsules that containthe active substance together with diluents, for example lactose,dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, andlubricants, for example silica, talcum, stearic acid or salts thereof,such as magnesium or calcium stearate, and/or polyethylene glycol;tablets also contain binders, for example magnesium aluminium silicate,starches such as maize, wheat, rice or arrowroot starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and, if desired, disintegrating agents, forexample starches, agar, alginic acid or a salt thereof, such as sodiumalginate, and/or effervescing mixtures, or adsorbents, dyestuffs,flavouring substances and sweeteners. Also, the new pharmacologicallyactive compounds can be used in the form of injectable, for exampleintravenously administrable, preparations or in the form of infusionsolutions. Solutions of this type are preferably isotonic aqueoussolutions or suspensions, wherein these can be produced before use, forexample, from lyophilised preparations that contain the active substancealone or together with a carrier, for example mannitol. Thepharmaceutical preparations may be sterilised and/or containauxiliaries, for example preservatives, stabilisers, wetting agentsand/or emulsifiers, solubilisers, salts for regulating the osmoticpressure and/or buffers. The pharmaceutical preparations of theinvention which, if desired, may contain other pharmacologicallyvaluable substances are produced in a manner known per se, for exampleby means of conventional mixing, granulating, pill-coating, dissolvingor lyophilising processes and contain from approximately 0.1% to 100%,especially from approximately 1% to approximately 50%, in the case ofthe lyophilisates up to 100%, of the active substance.

Referring to the present description, organic radicals referred to as"lower", unless expressly defined, contain up to 7, preferably up to 4,carbon atoms; acyl radicals contain up to 20, preferably up to 12, andespecially up to 7, carbon atoms.

The following Examples serve to illustrate the invention; temperaturesare in degrees Centigrade. The following abbreviation is used: TLC=thinlayer chromatogram over silica gel

EXAMPLE 1 4-acetylthio-3-methyl-2-oxoazetidine (racemic cis and transcompound)

A solution of 0.33 ml of thioacetic acid in 4.5 ml of 1N sodiumhydroxide solution is added dropwise at room temperature under anitrogen atmosphere to a solution of 438 mg (3.06 mmoles) of4-acetoxy-3-methylazetidin-2-one (produced according to K. Clauss etal., Lieb, Ann. Chem., 1974, 539; racemic mixture of cis- andtrans-isomer in a ratio of 3:1; Mp 53°-65°) in 1.13 ml of water and 0.27ml of acetone, and the mixture is stirred at the same temperature for 3hours. The reaction mixture is exhaustively extracted with methylenechloride. The combined organic phases are dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is chromatographedover silica gel with toluene/ethyl acetate (4:1 to 3:2) and yields firstof all the pure trans-compound, then a mixture of the cis- andtrans-isomers of the title compound and subsequently the purecis-compound.

TLC: R_(f) =0.31 (cis-isomer); 0.36 (trans-isomer) (toluene/ethylacetate 2:3); IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 5.6,5.87, 8.65, 8.85 and 10.45μ. NMR spectrum (in CDCl₃ /100 Mc, in ppm):cis-compound: 6.2, 1H, wide (exchange with D₂ O); 5.45, 1H, d(J=5.5 Hz);3.5-3.9, 1H, m; 2.4, 3H, s; 1.3, 3H, d; trans-compound 6.5, 1H, wide(exchange with D₂ O); 4.93, 1H, d (J˜2.5 Hz); 3.0-3.4, 1H, m; 2.4, 3H,s; 1.42, 3H, d.

EXAMPLE 2 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-hydroxyaceticacid p-nitrobenzyl ester (racemic cis-trans mixture)

A solution of 500 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzylester in a mixture of 10 ml of toluene and 2.5 ml of dimethylformamideis added at room temperature to 129 mg (0.81 mmole) of4-acetylthio-3-methyl-2-oxoazetidine (racemic cis-trans mixture). Afteradding freshly dried molecular sieves, the mixture is stirred undernitrogen for 15 hours at room temperature and subsequently for 2 hoursat 50°. The molecular sieves are filtered off, washed with toluene andthe filtrate and washing liquid are together ccncentrated by evaporationin vacuo. The residue is dried under high vacuum and chromatographedover silica gel with toluene/ethyl acetate (9:1 to 8:2). After elutionof the unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester amixture of the cis-trans isomers of the title compound having thefollowing physico-chemical properties is eluted:

TLC : R_(f) =0.38 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.85, 5.62, 5.7, 5.9, 6.2, 6.55, 7.4 and 8.25μ.

EXAMPLE 32-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic cis-trans mixture)

(a) A solution of 225 mg of2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-hydroxyacetic acidp-nitrobenzyl ester (racemic cis-trans mixture) in 5 ml of absolutedioxan is added to a solution of 1 g of poly-Hunig base in 2.5 ml ofabsolute dioxan that has already been stirred for 30 minutes. Afteradding a solution of 0.175 ml of thionyl chloride in 1.5 ml of absolutedioxan, the reaction mixture is stirred for 100 minutes at roomtemperature under nitrogen The poly-Hunig base is filtered off andwashed with dioxan and the filtrate is concentrated by evaporation invacuo. TLC of the crude2-(4-acetvlthi-o-3-methyl-2-oxoazetidin-1-yl)-2-chloroacetic acidp-nitrobenzyl ester (racemic cis-trans mixture): R_(f) =0.62(toluene/ethyl acetate 2:3).

(b) The crude 2-(acetylthio-3-methyl-2-oxo-azetidin-1-yl)-2-chloroaceticacid p-nitrobenzyl ester obtained is dissolved in 12 ml of absolutedioxan, 1 g of poly-Hunig base is added and the mixture is stirred for30 minutes, then 312 mg of triphenylphosphine are added and the mixtureis stirred under nitrogen for 15 hours at 50°. The poly-Hunig base isfiltered off, washed with dioxan and the filtrate and washing liquid aretogether concentrated by evaporation in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate and yields acis-trans mixture of the title compound having the followingphysico-chemical properties:

TLC : R_(f) =0.28 (toluene/ethyl acetate 2:3; IR spectrum (CH₂ Cl₂):absorption bands at 5.67, 5.9, 6.15, 6.55, 6.95, 7.4, 9.0 and 9.25μ.

EXAMPLE 4 2,6-dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester(racemic cis-trans mixture)

A catalytic amount of p-hydroxyquinone is added to a solution of 118 mgof2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic cis-trans mixture) in 50 ml ofabsolute toluene, and the mixture is stirred for 48 hours at 90° undernitrogen. The solvent is evaporated off in vacuo and the residue ischromatographed over silica gel with toluene/ethyl acetate (19:1). Acis-trans mixture (1:4) of the title compound is obtained in the form ofa yellowish oil having the following physico-chemical properties:

TLC : R_(f) =0.59 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.6, 5.85 6.3, 6.55, 7.4, 7.6, 8.3 and 9.25μ; NMRspectrum (in CDCl₃ /100 Mc, in ppm): 8.4-8.2, 2H; 7.75-7.76, 2H, m;5.7-5.2, 3H, m; 4.1-3.6, 1H, m; 2.4, 2.43, 3H, 2s; 1.6-1.4, 3H, 2d.

EXAMPLE 5 2,6-dimethyl-2-penem-3-carboxylic acid (racemic cis-transmixture)

2 ml of 0.2M aqueous sodium bicarbonate solution and 100 mg of 10%palladium/carbon catalyst are added to a solution of 47 mg (0.14 mmole)of 2,6-dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester (racemiccis-trans mixture 1:4) in 3 ml of absolute ethyl acetate and the mixtureis stirred at normal pressure for 40 minutes under hydrogen. Thecatalyst is filtered off from the hydrogenated mixture over diatomaceousearth, the residue is washed with 0.2M sodium bicarbonate solution andseveral times with ethyl acetate. The aqueous phase is washed withmethylene chloride, acidified with 5% aqueous citric acid solution andexhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate, filtered, concentrated byevaporation in vacuo and dried under high vacuum. The title compoundobtained (cis-trans mixture˜1:4) has the following physico-chemicalproperties:

TLC : R_(f) =0.28 (toluene/ethyl acetate/acetic acid 60:40:5); IRspectrum (CH₂ Cl₂): absorption bands at 3.5, 5.6, 5.95 and 6.3μ; NMRspectrum (DMSO d6/100 Mc, in ppm): 5.65, 1H, q; 3.3-3.9, 2H, m (+H₂ O);2.28, 3H, s, melting point 119°.

EXAMPLE 6 Sodium salt of 2,6-dimethyl-2-penem-3-carboxylic acid (raceniccis-trans mixture)

A solution of 50 mg of 2,6-dimethyl-2-penem-3-carboxylic acid in theequivalent amount of aqueous sodium bicarbonate solution is concentratedby evaporation in vacuo and dried under high vacuum.

EXAMPLE 7 4-acetylthio-3-methyl-2-oxoazetidine (racemic trans-compound)

A solution of 1.5 ml of thioacetic acid in 20.5 ml of 1N sodiumhydroxide solution is added dropwise at room temperature, undernitrogen, to a solution of 2 g of 4-acetoxy-3-methyl-azetidin-2-one(produced according to K. Clauss et. al., Lieb. Ann. Chem., 1974, 539;racemic mixture of cis- and trans-isomer in a ratio of 3:1, Mp. 53°-65°)in 5.16 ml of water and 1.25 ml of acetone, and the mixture is stirredat the same temperature for 3 hours. The reaction mixture isexhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated by evaporation invacuo. The residue is chromatographed over 150 g of silica gel withtoluene/ethyl acetate (9:1) and yields the almost pure trans-isomer ofthe title compound with the following physico-chemical properties:

TLC: 0.38 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂): absorptionbands at 2.95, 5.6, 5.87, 7.37, 7.45, 8.62 and 8.82μ. NMR spectrum (inCD Cl₃ /100 Mc, in ppm) 6.55, 1H, m (exchange with D₂ O); 4.9, 1H, d,J=2 Hz; 3.35-3.05, 1H, m; 2.38, 3H, s; 1.4, 3H, d, J=7 Hz. Subsequentlya mixture of the cis- and trans-isomers is isolated.

EXAMPLE 8 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-hydroxyaceticacid p-nitrobenzyl ester (racemic trans-compound)

At room temperature a solution of 5 g of 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester in a mixture of 100 ml of toluene and 25 ml ofdimethylformamide is added to 1.35 g (8.49 mmole) of4-acetylthio-3-methyl-2-oxoazetidine (racemic trans-compound). Afteradding freshly dried molecular sieves the mixture is stirred undernitrogen for 15 hours at room temperature and then for 2 hours at 50°.The molecular sieves are filtered off, washed with toluene and thefiltrate and washing liquid are together concentrated by evaporation invacuo. The residue is dried under high vacuum and chromatographed over100 g of silica gel with toluene/ethyl acetate (9:1). After elution ofthe unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, thetitle compound having the following physicochemical properties iseluted:

TLC : R_(f) =0.33 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.85, 5.6, 5.7, 5.87, 6.2, 6.52, 7.4, 8.28 and9-9.2μ.

EXAMPLE 92-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-triphenylph-os-phoranylideneaceticacid p-nitrobenzyl ester racemic trans-compound

(a) A solution of 3 g of2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-hydroxyacetic acidp-nitrobenzyl ester (racemic trans-compound) in 75 ml of absolute dioxanis added to a solution of 13.5 g of poly-Hunig base in 35 ml of absolutedioxan that has already been stirred for 30 minutes. After adding asolution of 2.4 ml of thionyl chloride in 22.4 ml of absolute dioxan,the reaction mixture is stirred for 100 minutes at room temperatureunder nitrogen. The poly-Hunig base is filtered off, washed with dioxanand the filtrate is concentrated by evaporation in vacuo.

TLC of the crude2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-chloroacetic acidp-nitrobenzyl ester (racemic trans-compound): R_(f) =0.59 (toluene/ethylacetate 2:3).

(b) The resulting crude2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-chloroacetic acidp-nitrobenzyl ester is dissolved in 175 ml of absolute dioxan, 13.5 g ofpoly-Hunig base are added, then 4.2 mg of triphenylphosphine, and themixture is stirred for 15 hours at 50° under nitrogen. The poly-Hunigbase is filtered off, washed with dioxan and the filtrate and washingliquid are together concentrated by evaporation in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate and yieldsthe trans-title compound with the following physico-chemical properties:

TLC: R_(f) =0.24 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂)absorption bands at 5.67, 5.9, 6.15, 6.55, 7.4 and 9.0μ.

EXAMPLE 10 2,6-dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester(racemic trans-compound)

A catalytic amount of p-hydroxyquinone is added to a solution of 363 mgof2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-3-triphenylphospohoranylideneaceticacid p-nitrobenzyl ester (racemic trans-compound) in 180 ml of absolutetoluene and the mixture is stirred under nitrogen for 48 hours at 90°.The solvent is evaporated off in vacuo and the residue ischromatographed over 20 g of silica gel with toluene/ethyl acetate(19:1). The trans-title compound is obtained in the form of yellowishcrystals having a melting point of 141°-143° and the followingphysico-chemical properties:

TLC: R_(f) =0.6 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂)absorption bands at 3.4, 5.57, 5.82, 6.27, 6.55, 7.4, 7.6, 8.3 and9.22μ; NMR spectrum (in CDCl₃ /100 Mc, in ppm): 8.25-8.15, 2H, m;7.65-7.56, 2H, m; 5.55-5.12, 3H, m+d (J=1.5 Hz); 3.9-3.6 1H, m; 2.36,3H, s: 1.5, 3H, d.

EXAMPLE 11 2,6-dimethyl-2-penem-3-carboxylic acid (racemictrans-compound)

3 ml of 0.2N aqueous sodium bicarbonate solution and 150 mg of 10%palladiun/carbon catalyst are added to a solution of 80 mg (0.24 mmole)of 2,3-dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester (racemictrans-compound) in 5 ml of absolute ethyl acetate, and the mixture isstirred at normal pressure for 50 minutes under hydrogen. The catalystis filtered off from the hydrogenated mixture over diatomaceous earthand washed with 0.2N sodium bicarbonate solution and several times withethyl acetate. The aqueous phase is washed with methylene chloride,acidified with 5% aqueous citric acid solution and exhaustivelyextracted with methylene chloride. The combined organic phases are driedover sodium sulphate, filtered, concentrated by evaporation in vacuo anddried in a high vacuum. The resulting title compound has the followingphysico-chemical properties:

Melting Point 119° (decomposition): TLC: R_(f) =0.3 (toluene/ethylacetate/acetic acid 60:40:5); IR spectrum (KBr): absorption bands at3.3-3.5, 5.62, 6.0, 6.35, 6.95, 7.55 and 7.85μ; NMR spectrum (DMSOd6/100 Mc, in ppm): 5.38, 1H, d, (J=1.5 Hz); 3.7, 1H, m: 3.4, 1H, m(exchange with D₂ O); 2.28, 3H, s; 1.34, 3H, d.

EXAMPLE 12 4-acetylthio-3-isopropyl-2-oxoazetidine (racemictrans-compound)

A solution of 0.52 ml of thioacetic acid in 7 ml of 1N sodium hydroxidesolution is added dropwise at room temperature under a nitrogenatmosphere to a solution of 750 mg (4.38 mmole) of4-acetoxy-3-isopropylazetidin-2-one (racemic mixture of cis- andtrans-isomer in the ratio of 1:3) in 3.6 ml of water and 0.9 ml ofacetone and the mixture is stirred at the same temperature for 75minutes. The reaction mixture is exhaustively extracted with methylenechloride. The combined organic phases are dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is chromatographedover 40 g of silica gel with toluene/ethyl acetate (4:1) and yields thetrans-title compound.

TLC: R_(f) =0.4 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 2.95, 3.37, 5.62, 5.87 and 8.8μ. NMR spectrum (inCDCl₃ /100 Mc, in ppm): 6.35, 1H, m (exchange with D₂ O); 5.04, 1H, d(J=2.5 Hz); 3.0, 1H, m; 2.37, 3H, s; 2.1, 1H, m; 1.05, 3H, m.

The starting material is produced as follows: (a) A mixture of 172.28 g(216.5 ml, 2 mole) of isovaleraldehyde, 306 g (283 ml) of aceticanhydride and 24 g of freshly molten potassium acetate is refluxed for17 hours. The cooled mixture is washed with 5% sodium carbonate solutionuntil the organic phase reacts neutrally. After washing with water anddrying over magnesium sulphate the oil obtained is distilled.3-methylbut-1-enyl acetate (cis-trans mixture 1:4) having a boilingpoint of 135°-140°/760 mmHg is obtained. (b) A solution of 8.72 ml ofN-chlorosulphonyl isocyanate in 10 ml of absolute methylene chloride isadded dropwise to a solution of 12.8 g (0.1 mole) of 3-methylbut-1-enylacetate (cis-trans mixture 1:4) in 40 ml of absolute methylene chlorideat room temperature under nitrogen. After 4 hours the reaction mixtureis slowly poured into a mixture of 10 ml of water, 45 g of ice, 24 g ofsodium bicarbonate and 8.3 g of sodium sulphite, the temperature beingmaintained between 0° and 5° by the occasional addition of ice. Afterapproximately 30 minutes the organic phase reacts neutrally, whereuponit is separated off. The aqueous phase is extracted with methylenechloride. The organic phases are combined, dried over sodium sulphateand concentrated by evaporation in vacuo. The residue is chromatographedover silica gel with toluene/ethyl acetate and yields a cis-transmixture of 4-acetoxy-3-isopropylazetidin-2-one in a ratio ofapproximately 1:3.

TLC: R_(f) =0.3 (toluene/ethyl acetate 2:3); IR spectrum (in methylenechloride): absorption bands at 2.95, 3.37, 5.6, 5.72, 7.32, 8.1, 9.7 and10.2μ; NMR spectrum (CDCl₃ /100 Mc, in ppm): 6.75, 1H, m (exchange withD₂ O); 5.85, d, J=4.5 Hz (cis) and 5.6, d, J =1.5 Hz (trans), 1H; 3.03,1H, m; 2.1, 3H, 2s; 2.3-1.8, 1H, m; 1.1, 6H, m.

EXAMPLE 132-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-hydroxyacetic acidp-nitrobenzyl ester (racemic trans-compound)

1.9 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are added atroom temperature to a solution of 616 mg (3.3 mmole) of4-acetylthio-3-isopropyl-2-oxoazetidine (racemic trans-compound) in 48ml of toluene and 10.5 ml of dimethylformamide. After adding freshlydried molecular sieves the mixture is stirred under nitrogen for 15hours at room temperature and then for 2 hours at 50°. The molecularsieves are filtered off, washed with toluene and the filtrate andwashing liquid are together concentrated by evaporation in vacuo. Theresidue is dried in a high vacuum and chromatographed over 60 g ofsilica gel with toluene/ethyl acetate (9:1). The two transisomers of thetitle compound, contaminated slightly by unreacted2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, are obtained with thefollowing physicochemical properties:

TLC: R_(f) =0.4 and 0.37 (toluene/ethyl acetate 2:3); IR spectrum (CH₂Cl₂): absorption bands at 5.62, 5.68, 6.55 and 7.42μ.

EXAMPLE 142-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic trans-compound)

(a) A solution of 1.175 g of2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-hydroxyacetic acidp-nitrobenzyl ester (racemic trans-compound) in 21 ml of absolute dioxanis added to a solution of 3.8 g of poly-Hunig base in 10 ml of absolutedioxan that has already been stirred for 30 minutes. After the dropwiseaddition of a solution of 0.67 ml of thionyl chloride in 6.3 ml ofabsolute dioxan, the reaction mixture is stirred for 90 minutes at roomtemperature under nitrogen. The poly-Hunig base is filtered off, washedwith dioxan and the filtrate is concentrated by evaporation in vacuo.The resulting crude2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-chloroacetic acidp-nitrobenzyl ester (racemic trans-compound) can be used in the nextstep without further purification.

(b) The resulting crude2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-chloroacetic acidp-nitrobenzyl ester is dissolved in 50 ml of absolute dioxan, 3.8 g ofpoly-Hunig base are added, the mixture is stirred for 30 minutes, then1.18 g of triphenylphosphine are added and the mixture is stirred for 15hours at 50° under nitrogen. The poly-Hunig base is filtered off, washedwith dioxan and the filtrate and washing liquid are togetherconcentrated by evaporation in vacuo. The residue is chromatographedover 60 g of silica gel with toluene/ethyl acetate 7:3 and yields thetrans-title compound with the following physico-chemical properties:

TLC: R_(f) =0.25 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 5.7, 5.9, 6.17, 6.55, 7.42 and 9.05μ.

EXAMPLE 15 2-methyl-6-isoprooyl-2-penem-3-carboxylic acid p-nitrobenzylester (racemic trans-compound)

A catalytic amount of p-hydroxyquinone is added to a solution of 660 mgof 2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylideneacetic acidp-nitrobenzyl ester (racemic trans-compound) in 300 ml of absolutetoluene, and the mixture is stirred for 48 hours at 90° under nitrogen.The solvent is evaporated off in vacuo and the residue ischromatographed over 30 g of silica gel with toluene/ethyl acetate(19:1). The trans-title compound is obtained, by crystallisation fromdiethyl ether/methylene chloride, in the form of colourless crystalshaving the following -physico-chemical properties: melting point:138°-139°; TLC: R_(f) =0.59 (toluene/ethyl acetate 2:3): IR spectrum(CH₂ Cl₂) absorption bands at 5.57, 5.82, 6.27, 6.55, 7.4 and 7.6μ; NMRspectrum (in CDCl₃ /100 Mc, in ppm): 8.3-8.2, 2H, m; 7.5-7.4, 2H, m15.75-5.1, 3H, m; 3.6-3.5, 1H, dd, J=8 and 1.5 Hz; 2.35, 3H, s; 1.07, 6H,m.

EXAMPLE 16 2-methyl-6-isopropyl-2-penem-3-carboxylic acid (racemictrans-compound)

4 ml of 0.2N aqueous sodium bicarbonate solution and 50 mg of 10%palladium/carbon catalyst are added to a solution of 100 mg of2-methyl-6-isopropyl-2-penem-3-carboxylic acid p-nitrobenzyl ester(racemic trans-compound) in 7 ml of absolute ethyl acetate, and themixture is stirred at normal pressure for 30 minutes under hydrogen. Thecatalyst is filtered off from the hydrogenated mixture over diatomaceousearth and washed with 0.2N sodium bicarbonate solution and several timeswith ethyl acetate. The aqueous phase is washed with methylene chloride,acidified with 5% aqueous citric acid solution and exhaustivelyextracted with methylene chloride. The combined organic phases are driedover sodium sulphate, filtered, concentrated by evaporation in vacuo anddried in a high vacuum. The resulting title compound has the followingphysico-chemical properties:

Melting Point 140°-143° (decomposition); TLC: R_(f) =0.37 (toluene/ethylacetate/acetic acid 60:40:5); IR spectrum (KBr): absorption bands at3.5, 5.62, 6.0, 6.35, 6.9, 7.52, 7.8 and 8.0μ; NMR spectrum (DMSO d6/100Mc, in ppm): 5.52, 1H, d, J =1.5 Hz; 3.56, 1H+2 H₂ O, dd, J=1.5 and 7.5Hz; 2.26, 3H; s; 2.04, 1H, m; 1-0.9, 6H, m.

EXAMPLE 17 4-acetylthio-3-benzyl-2-oxoazetidine (racemic trans-compound)

A solution of 0.76 g (10 mmole) of thioacetic acid in 10 ml of 1N sodiumhydroxide solution is added dropwise to a solution of 2.19 g (10 mmole)of 4-acetoxy-3-benzylazetidin-2-one (racemic mixture of cis- andtrans-isomer in the ratio of 9:13) in 10 ml of dioxan at roomtemperature under a nitrogen atmosphere, and the mixture is stirred atthe same temperature for 3 hours. The reaction mixture is exhaustivelyextracted with methylene chloride. The combined organic phases are driedover sodium sulphate and concentrated bv evaporation in vacuo. Theresidue is chromatogra.ohed over silica gel with toluene/ethyl acetate(9:1) and yields a cis-trans mixture of the title compound in the ratioof 2:10. By recrystallisation from methylene chloride/hexane at -10° thepure trans-compound having a melting point of 42°-43° is obtained.

TLC: R_(f) =0.52 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂)absorption bands at 2.95, 5.65, 5.95, 7.40, 8.8 and 10.5μ; NMR spectrum(in CDCl₃ /100 Mc, in ppm): 7.24, 5 H, m; 1 6.60, 1H, b; 4.99, 1H, d,J=2 Hz; 3.45, 1H, dq, J_(B) =8 Hz, J_(C) =6 Hz, J_(D) =2 Hz; 3.18, 1H,q, J_(A) =15 Hz, J_(C) =6 Hz; 3.00, 1H, q, J_(A) =15 Hz, J_(B) =8 Hz:2.30, 3H, s.

The starting material is produced as follows

(a) A mixture of 25 g (0.186 mole) of 3-phenylpropionaldehyde, 50 ml ofacetic anhydride and 50 ml of pyridine is stirred for 15 hours at 100°and then concentrated by evaporation in a water jet vacuum. The residueis dissolved in methylene chloride, washed with 5% aqueous sodiumbicarbonate solution and citric acid solution, dried over sodiumsulphate and freed of solvent in vacuo. The residue is distilled invacuo. 3-phenylprop-1-enyl acetate (cis-trans mixture 1:1) having aboiling point of 61°-65°/1 mm Hg is obtained.

(b) A mixture, prepared at 0°, of 17.6 g (0.1 mole) of3-phenylprop-1-enyl acetate (cis-trans mixture 1:1) and 14.15 g (0.1mmole) of N-chlorosulphonyl isocyanate is stirred for 6 hours at10°-15°. The reaction mixture is diluted with 100 ml of cold methylenechloride and is slowly poured into a mixture of 10 ml of water, 45 g ofice, 24 g of sodium bicarbonate and 17 g of sodium sulphite. Afterfiltering, the organic phase is separated off. The aqueous phase isextracted with methylene chloride. The organic phases are combined,dried over sodium sulphate and concentrated by evaporation in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate9:1 to 8:2, and yields a cis-trans mixture of4-acetoxy-3-benzylazetidin-2-one in a ratio of 9:13.

TLC: R_(f) =0.5 (toluene/ethyl acetate 1:1); IR spectrum (in methylenechloride): absorption bands at 2.95, 5.6, 5.75, 7.35, 8.15, 8.65, 9.6,and 10.25μ; NMR spectrum (CDCl₃ /100 Mc, in ppm): 2.04, s and 2.08, s,3H; 2.95-3.15, 2H, m: 3.35-3.8 1H, m 5.50, 0.6 H, d, J=2 Hz (trans);5.86, 0.4 H, d, J=4 Hz (cis); further signals at 6.80-7.45.

EXAMPLE 18 2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-hydroxyaceticacid p-nitrobenzyl ester (racemic trans-compound)

2 g of 2-ethoxy-2-hydroxyacetic acid p-nitropenzyl ester are added atroom temperature to a solution of 0.73 g (3.1 mmole) of4-acetylthio-3-benzyl-3-oxoazetidine (racemic trans-compound) in 50 mlof toluene and 20 ml of dimethylformamide. After adding freshly driedmolecular sieves, the mixture is stirred under nitrogen overnight atroom temperature and then for 2 hours at 50°. The molecular sieves arefiltered off, washed with toluene and the filtrate and washing liquidare together concentrated by evaporation in vacuo. The residue is driedin a high vacuum and chromatographed over silica gel with toluene/ethylacetate (9:1 to 4:1). The two trans-isomers of the title compound,slightly contaninated with unreacted 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester, are obtained with the following physico-chemicalproperties: TLC: R_(f) =0.57 (toluene/ethyl acetate 1:1); IR spectrum(CH₂ Cl₂): absorption bands at 2.85, 5.60, 5.70, 6.00, 6.20, 6.55, 7.40,8.25, 9.00 and 11.75μ.

EXAMPLE 19 2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-trichenylphosphoranylideneacetic acidp-nitrobenzyl ester (racemic trans-compound)

(a) 6 g of poly-Hunig base are added to a solution of 1.5 g of2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-hydroxyacetic acidp-nitrobenzyl ester (racemic trans-compound) in 20 ml of dry dioxan.After dropwise addition of a solution cf 1.5 ml of thionyl chloride in10 ml of dioxan, the reaction mixture is stirred for 60 minutes at roomtemperature under nitrogen. The poly-Hunig base is filtered off, washedwith dioxan and the filtrate is concentrated by evaporation in vacuo.The resulting crude2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-chloroacetic acid-p-nitrobenzyl ester (racemic trans-compound) can be used in the nextstep without further purification.

(b) The crude2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-chloroacetic acidp-nitrobenzyl ester obtained is dissolved in 20 ml of dry dioxan, 6 g ofpoly-Hunig base are added, the mixture is stirred for 30 minutes, then1.5 g of triphenylphosphine are added and the mixture is stirredovernight at 50° under nitrogen. The poly-Hunig base is filtered off,washed with dioxan and the filtrate and washing liquid are togetherconcentrated by evaporation in vacuo. The residue is chromatographedover silica gel with toluene/ethyl acetate (9:1 to 1:1) and yields thetrans-title compound with the following physico-chemical properties:

TLC: R_(f) =0.50 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 5.7, 5.9, 6.2, 6.55, 7.00, 7.42, 9.05 and 11.75μ.

EXAMPLE 20 2-methyl-6-benzyl-2-penem-3-carboxylic acid p-nitrobenzylester (racemic trans-compound)

A catalytic amount of p-hydroxyquinone is added to a solution of 0.90 g(1.3 mmole) of2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic trans-compound) in 50 ml of drytoluene and the mixture is stirred under nitrogen for 2 days at 90°. Thesolvent is evaporated off in vacuo and the residue is chromatographedover silica gel with toluene/ethyl acetate (9:1). The trans-titlecompound is obtained by crystallisation from methylene chloride/diethylether and has the following physico-chemical properties:

Melting Point: 182°-183°; TLC: R_(f) =0.85 (toluene/ethyl acetate 1:1):IR spectrum (CH₂ Cl₂): absorption bands at 5.60, 5.85, 6.30, 6.55, 7.4,7.6, 8.25, 8.55, 9.25 and 11.70μ; NMR spectrum (CDCl₃ /100 Mc, in ppm):2.36, 3H, s; 3.12, 1H, dd, J_(A) =14 Hz, J_(B) =9 Hz, 3.34, 1H, dd,J_(A) =14 Hz, J_(C) =6 Hz; 4.03, 1H, dq, J_(B) =9 Hz, J_(C) =6 Hz, J_(D)=2 Hz: 5.40, 1H, d, J_(D) =2 Hz; 5.25, 1H, d, J =14 Hz; 5.45, 1H, d, J=14 Hz; 7.30, 5H, m; 7.66, 2H, d, J=9 Hz; 8.27, 2H, d, J=9 Hz.

EXAMPLE 21 2-methyl-6-benzyl-2-penem-3-carboxylic acid (racemictrans-compound)

8 ml of 0.2M aqueous sodium bicarbonate solution and 400 mg of 10%palladium/carbon catalyst are added to a solution of 200 mg of2-methyl-6-benzyl-2-penem-3-carboxylic acid p-nitrobenzyl ester (racemictrans-compound) in 12 ml of absolute ethyl acetate and the mixture isstirred at normal pressure for 60 minutes under hydrogen. The catalystis filtered off from the hydrogenated mixture over diatomaceous earth.The aqueous phase is separated off, acidified with 5% aqueous citricacid solution and exhaustively extracted with methylene chloride. Thecombined organic phases are dried over sodium sulphate, filtered,concentrated by evaporation in vacuo and dried in a high vacuum. Theresulting title compound has the following physico-chemical properties:

TLC: R_(f) =0.31 (toluene/ethyl acetate/acetic acid 60:40:5);IR spectrum(KBr): absorption bands at 3.20-4.30 b, 5.65, 6.0, 6.35, 6.9, 7.5, 7.9and 8.2μ.

EXAMPLE 22: 4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidine(racemic trans-compound)

A solution of 230 mg of potassium ethyl trithiocarbonate in 1.5 ml ofwater is added dropwise at room temperature, in a nitrogen atmosphere,to a solution of 195 mg (1.14 mmole) of4-acetoxy-3-isopropylazetidin-2-one (racemic mixture of cis- andtrans-isomer in the ratio of 1:3) in 1 ml of water and 0.2 ml of acetoneand the mixture is stirred at the same temperature for 120 minutes. Thereaction mixture is exhaustively extracted with methylene chloride. Thecombined organic phases are dried over sodium sulphate and concentratedby evaporation in vacuo. The residue is chromatographed over 12 g ofsilica gel with toluene/ethyl acetate (9:1) and yields the trans-titlecompound. Melting point: 65°-66° TLC: R_(f) =0.5 (toluene/ethyl acetate2:3]; IR spectrum (CH₂ Cl₂): absorption bands at 2.95, 3.37, 5.62 and9.25μ. NMR spectrum (in CDCl₃ /100 Mc, in ppm): 6.65, 1H, m (exchangewith D₂ O); 5.4, 1 H, d (J=2.5 Hz): 3.39, 2H, q; 3.05, 1H, m; 2.15, 1H,m: 1.38, 3H, t; 1.1, 6H, m.

EXAMPLE 232-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-hydroxyaceticacid p-nitrobenzyl ester (racemic trans-compound)

311 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are added atroom temperature to a solution of 137 mg (0.55 mmole) of4-ethylthiothiocarbonyltho-3-isopropyl-2-oxoazetidine (racemictrans-compound) in 8 ml of toluene and 2 ml of dimethylformanide. Afteradding freshly dried molecular sieves, the mixture is stirred undernitrogen for 15 hours at room temperature and then for 2 hours at 50°.The molecular sieves are filtered off, washed with toluene and thefiltrate and washing liouid are together concentrated by evaporation invacuo. The residue is dried in a high vacuum and chromatographed over 80g of silica gel with toluene/ethyl acetate (9:1). The two trans-isomersof the title compound, contaminated slightly by unreacted2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are obtained with thefollowing physico-chemical properties:

TLC: R_(f) =0.4 (toluene/ethyl acetate 2:3]; IR spectrum (CH₂ Cl₂):absorption bands at 5.62, 5.7, 6.55, 7.42, 8.2 and 9.2μ.

EXAMPLE 242-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-triphenylphosohoranylideneaceticacid p-nitrobenzyl ester (racemic transcompound)

A solution of 606 mg of2-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-hydroxyaceticacid p-nitrobenzyl ester (racemic trans-compound) in 6 ml of absolutetetrahydrofuran is cooled to -15°, while stirring 0.16 ml (2.23 mmole)of thionyl chloride and then, slowly, a solution of 0.31 ml oftriethylamine in 0.3 ml of absolute tetrahydrofuran are added. Thereaction mixture is stirred for 1 hour at 0°, 30 ml of cold methylenechloride are added and the mixture is washed with ice-cold 2Nhydrochloric acid. The organic phase is washed with water until there isneutral reaction, then is dried with sodium sulphate and concentrated byevaporation in vacuo. The resulting crude2-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-chloroaceticacid p-nitrobenzyl ester is dissolved in 1.5 ml of dry tetrahydrofuran,0.71 g of triphenylphosphine is added and the mixture is stirredovernight at room temperature under a nitrogen atomsphere. The reactionmixture is diluted with methylene chloride, washed in succession withsaturated aqueous sodium bicarbonate solution and water, dried oversodium sulphate and concentrated by evaporation in vacuo. The residueyields the title compound by chromatography over silica gel withtoluene/ethyl acetate (9:1).

TLC: R_(f) =0.5 (toluene/ethyl acetate 2:3); IR spectrum (CH₂ Cl₂):absorption bands at 3.4, 5.7, 6.15, 6.55, 7.45, 9.05 and 9.25μ.

EXAMPLE 25 2-ethylthio-6-isopropyl-2-penem-3-carboxylic acidp-nitrobenzyl ester (racemic transcompound)

A catalytic amount of p-hydroxyquinone is added to a solution of 600 mg(0.855 mmole) of2-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic trans-compound) in 250 ml of absoluteo-xylene and the mixture is stirred under reflux in a nitrogenatmosphere for 48 hours. The solvent is evaporated off in vacuo and theresidue is chromatographed over 35 g of silica gel with toluene/ethylacetate (19:1). The trans-title compound is obtained in the form ofcolourless crystals by crystallisation from diethyl ether/methylenechloride;

TLC: R_(f) =0.62 (toluene/ethyl acetate 2:3); IR spectrum, (CH₂ Cl₂):absorption bands at 5.57, 5.9, 6.55, 7.4 and 7.52μ.

EXAMPLE 26 2-ethylthio-6-isopropyl-2-penem-3-carboxylic acid (racemictrans-compound)

4 ml of 0.2N aqueous sodium bicarbonate solution and 150 mg of 10%palladium/carbon catalyst are added to a solution of 100 mg of2-ethylthio-6-isopropyl-2-penem-3-carboxylic acid p-nitrobenzyl ester(racemic trans-compound) in 6 ml of absolute ethyl acetate and themixture is stirred at normal pressure for 240 minutes under hydrogen.The catalyst is filtered off from the hydrogenated mixture overdiatomaceous earth, then washed once with 0.2N sodium bicarbonatesolution and several times with ethyl acetate. The aqueous phase iswashed with methylene chloride, acidified with 5% aqueous citric acidsolution and exhaustively extracted with methylene chloride. Thecombined organic phases are dried over sodium sulphate, filtered,concentrated by evaporation in vacuo and dried in a high vacuum. Theresulting title compound has the following physicochemical properties:

TLC: R_(f) =0.35 (toluene/ethyl acetate/acetic acid 60:40:5); IRspectrum (KBr): absorption bands at 3.5, 5.62, 6.0, 6.75, 6.9, 7.52,7.9, 8.15 and 8.9μ.

EXAMPLE 27 6-diazopenicillanic acid methyl ester

Analogously to German Offenlegungsschrift No. 2 305 972, 1.01 g of crude6β-(N-nitroso)phenoxyacetamidopenicillanic acid methyl ester (producedaccording to U.S. Pat. No. 3,880,837) are dissolved at room temperaturein 75 ml of absolute chloroform and aftcr adding 200 ml of saturatedaqueous sodium bicarbonate solution the mixture is stirred for 9 hoursat a temperature of between 10 and 20°. The chloroform solution isseparated off, washed with water and dried over sodium sulphate. Afterevaporating off the solvent in vacuo at room temperature, the crudediazo compound is obtained in the form of an oil. It can be used in thenext reaction without further purification.

IR spectrum (in methylene chloride): characteristic absorption bands at3.40, 4.80, 5.55, 5.70, 6.23, 6.50, 6.68, 7.75, 8.22, 8.85, 10.6 and11.42μ.

EXAMPLE 28 6α-methoxypenicillanic acid methyl ester

5 ml of methanol and a few drops of 30% aqueous perchloric acid areadded to a solution of 2 g of crude 6-diazopenicillanic acid methylester in 15 ml of absolute methylene chloride and the mixture is stirredfor 15 minutes at room temperature. The reaction mixture is diluted with30 ml of methylene chloride and washed in succession with aqueous sodiumbicarbonate solution, water and sodium chloride solution, dried oversodium sulphate and concentrated by evaporation in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1 and 4:1)and yields the slightly contaminated title compound.

IR spectrum (in methylene chloride): characteristic bands at 3.40, 5.63,5.70, 6.90, 7.30, 7.68, 8.25, 8.47, 8.90, 9.15, 9.70 and 9.86μ.

EXAMPLE 29 6α-methoxypenicillanic acid methyl ester 1-oxide

A solution of 473 mg of 6α-methoxypenicillanic acid methyl ester in 10ml of methylene chloride is cooled to 0°, 334 mg of m-chloroperbenzoicacid are added and the resulting suspension is stirred for 1 hour at thesame temperature. The reaction mixture is diluted with 50 ml ofmethylene chloride, washed twice with aqueous sodium bicarbonatesolution and with water, and dried over sodium sulphate. The solvent isevaporated off in vacuo and the residue is chromatographed over silicagel. With toluene/ethyl acetate (9:1 and 4:1) the title compound isobtained in the form of a white powder. An analytical sample isrecrystallised from methylene chloride/diethyl ether/pentane and has thefollowing physico-chemical properties:

Mp. 121°; α_(D) =+281°±1°; IR spectrum (in methylene chloride):characteristic absorption bands at 3.40, 5.58, 5.70, 6.85, 6.97, 7.75,8.20, 8.90 and 9.45μ.

EXAMPLE 302-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylenebutyricacid methyl ester

A solution of 307 mg of 6α-methoxypenicillanic acid methyl ester 1-oxideis dissolved in 10 ml of toluene, 196.57 mg of 2-mercaptobenzthiazoleare added and the mixture is refluxed for 90 minutes. The solvent isdistilled off in vacuo and the residue is chromatographed over silicagel. By elution with toluene/ethyl acetate (9:1) the title compound isobtained in the form of a colourless oil. IR spectrum (in methylenechloride): characteristic bands at 3.40, 5.62, 5.72, 6.68, 6.85, 7.02,7.25, 7.50, 8.10, 8.20, 8.60, 8.95, 9.55, 9.92 and 10.92μ.

EXAMPLE 312-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxv-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester

0.1 ml of triethylamine is added to a solution of 432 mg of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylenebutyricacid methyl ester in 25 ml of methylene chloride and the mixture isstirred at room temperature for 100 minutes. The reaction mixture isdiluted with methylene chloride, washed twice with aqueous citric acidsolution and water, dried over sodiun sulphate and freed of solvent invacuo. The residue is purified by chromatography over silica gel withtoluene/ethyl acetate (9:1 and 4:1) and yields the title compound in theform of an oil.

IR spectrum (in methylcne chloride): characteristic absorption bands at3.40, 5.63, 5.78, 6.85, 7.03, 7.23, 7.32, 7.70, 8.15, 8.87, 9.00, 9.25and 9.92μ.

EXAMPLE 322-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester

A solution of 372 mg of2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester in 10 ml of dimethylformamide is cooled to -20°, 10 mlof a solution of 2 g of sodium borohydride in 200 ml ofdimethylformamide are added and the mixture is stirrcd at the sametemperature for 30 minutes. 5 ml of freshly distilled acetyl bromide areadded to the reaction mixture and the mixture is further stirred for 110minutes at 0°. After adding 150 ml of benzene, the reaction mixture iswashed in succession with sodium bicarbonate solution and water, driedover sodium sulphate and concentrated by evaporation in vacuo. Theresidue yields, after chromatography over silica gel with toluene/ethylacetate (9:1), the title compound in the form of a slightly yellowishoil.

IR spectrum (in methylene chloride): characteristic absorption bands at3.40, 5.63, 5.77, 5.83, 6.10, 6.95, 7.20, 7.30, 7.70, 8.12, 8.90, 9.20,9.90, 10.20, 10.50 and 11.83μ.

Example 332-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-oxoacetic acidmethyl ester

3 equivalents of ozone are conveyed through a solution, cooled to -30°,of 87 mg (0.31 mmole) of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester in 5 ml of ethyl acetate. The reaction mixture isdiluted with 30 ml of methylene chloride and is shaken for 2 minuteswith a 10% aqueous sodium bisulphite solution. The organic phase isseparated off, washed with saturated sodium chloride solution, driedover sodium sulphate and concentrated by evaporation in vacuo.

IR spectrum of the resulting oily title compound (in methylenechloride): characteristic bands at 3.40, 5.47, 5.67, 5.82, 6.97, 7.33,8.10, 8.92, 9.88 and 10.40μ. The resulting product can be used in thenext step without further purification.

EXAMPLE 34 (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine

A solution of 71.20 mg of2[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-oxoacetic acidmethyl ester (crude product) in 10 ml of 1% aqueous methanol is stirredovernight at room temperature. The reaction mixture is diluted withmethylene chloride, washed with water, dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is chromatographedover silica gel with toluene/ethyl acetate (9:1) and yields the titlecompound.

IR spectrum (in methylene chloride): characteristic absorption bands at2.95, 3.40, 5.60, 5.88, 7.00, 7.37, 7.52, 8.25, 8.70, 8.85, 10.5 and12.15μ.

EXAMPLE 352-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester

714 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 4 g ofmolecular sieve A4 are added to a solution of 245 mg of(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 8 ml oftoluene and 2 ml of dimethylformamide and the mixture is stirredovernight at room temperature. The molecular sieves are filtered offfrom the mixture and the filtrate is concentrated by evaporation invacuo. The residue is chromatographed over silica gel, and by elutionwith toluene/ethyl acetate (9:1 and 4:1) the title compound,contaminated with some glyoxylate, is obtained.

EXAMPLE 362-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

(a) A suspension of 2 g of poly-Hunig base in 8 ml of dioxan is stirredfor 30 minutes at room temperature, 832 mg of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester dissolved in 12 ml of dioxan are added and thenslowly a solution of 0.54 ml of thionyl chloride in 10 ml of dioxan isadded. The mixture is stirred for 2 hours at room temperature, thepoly-Hunig base is filtered off and the filtrate is concentrated byevaporation in vacuo. The residue is purified by chromatography oversilica gel with toluene/ethyl acetate (1:1) and yields the2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester in crude form.

(b) 812 mg of triphenylphosphine and 3 g of poly-Hunig base are added toa solution of 833 mg of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester in 50 ml of dioxan and the mixture is stirredovernight at 50°. The poly-Hunig base is removed by filtration and thefiltrate is concentrated by evaporation in vacuo. The residue ischromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and1:1) and yields the title comcound.

IR spectrum (in methylene chloride): characteristic absorption bands at3.40, 5.67, 5.85, 6.15, 6.55, 6.97, 7.42, 8.0 and 9.03μ.

EXAMPLE 37 (5R,6S)-2-methyl-6-methoxy-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 244 mg of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 100 ml of ahsolute toluene and the mixtureis stirred for 32 hours at 90° under nitrogen. The toluene is evaporatedoff in vacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (19:1). The title compound is obtained in the formof a solid white substance.

IR spectrum (in methylene chloride): characteristic absorption bands at3.40, 5.55, 6.30, 6.55, 7.03, 7.42, 7.60, 8.20, 8.42, 8.60, 8.90, 9.20,9.60 and 11.7μ; NMR spectrum (CDCl₃ /100 Mc, in ppm): 8.22, 2H, d, J=8Hz; 7.64, 2H, d, J=8 Hz; 5.53, 1H, d, J=2 Hz; 5.35, 2H, AB; 4.91, 1H, d,J=2 Hz; 3.57, 3H, s; 2.37, 3H, s.

EXAMPLE 38 (5R,6S)-2-methyl-6-methoxy-2-penem-3-carboxylic acid

75 mg of 10% palladium/carbon catalyst are added to a solution of 34 mgof (5R,6S)-2-methyl-6-methoxy-2-penem-3-carboxylic acid p-nitrobenzylester in a mixture of 2 ml of ethyl acetate and 2 ml of 2M sodiumbicarbonate solution, and the mixture is hydrogenated at roomtemperature for 1.5 hours under atmospheric pressure. The hydrogenatedmixture is filtered through diatomaceous earth and the filter residue iswashed with 1 ml of 2M aqueous sodium bicarbonate solution and ethylacetate. The aqueous phase is separated off from the filtrate, acidifiedwith 0.1M aqueous citric acid and extracted several times with methylenechloride. The combined methylene chloride extracts are dried over sodiumsulphate and concentrated by evaporation in vacuo.

IR spectrum (in methylene chloride) of the resulting crude titlecompound: characteristic absorption bands at 3.40, 5.57, 5.80, 5.95,6.30, 7.00, 8.20 and 9.90μ.

EXAMPLE 39 6α-phenoxyacetoxypenicillanic acid methyl ester

Analogously to D. Hauser and H. P. Sigg, Helv. Chim. Acta 50, 1327(1967), a solution of 7.4 g (20.3 mmole) of6β-(N-nitroso)-phenoxyacetamidopenicillanic acid methyl ester (crudeproduct according to U.S. Pat. No. 3,880,837) in 100 ml of benzene isstirred for 3 hours at 50° in a nitrogen atmosphere. The solvent isevaporated off -in vacuo and the residue is chromatographed over silicagel with toluene/ethyl acetate (9:1). The resulting oily product isrecrystallised from diethyl ether/hexane and yields the title compoundhaving a melting point of 71°; α_(D) =114'±1° (CHCl₃); IR spectrum (inmethylene chloride): characteristic absorption bands at 3.4, 5.6, 5.7,6.25, 6.69, 7.17, 8.26, 8.55, 9.05 and 9.18μ.

EXAMPLE 40: 6α-phenoxyacetoxypenicillanic acid methyl ester 1-oxide

1.1 g (1 equivalent) of 50% m-chloroperbenzoic acid are added inportions at 0° to a solution of 1.16 g (3.18 mmole) of6α-phenoxyacetoxypenicillanic acid methyl ester in 30 ml of absolutemethylene chloride. After addition is complete, the reaction mixture isstirred for 30 minutes at 0°, then diluted with methylene chloride,washed in succession with aqueous sodium bicarbonate solution, water andsodium chloride solution, and dried over sodium sulphate. Afterevaporating off the solvent the residue is chromatographed over silicagel with toluene/ethyl acetate (4:1). The title compound is obtained inthe form of a foam;

TLC: Rf=0.24 (toluene/ethyl acetate 1:1), IR spectrum (in methylenechloride): characteristic absorption bands at 3.33, 3.41, 5.57, 5.72,6.27, 6.72, 7.0, 8.25, 8.6, 9.21 and 9.46μ.

EXAMPLE 41:2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-3-methylenebutyricacid methyl ester

A solution of 1.01 (2.65 mmole) of 6α-phenoxyacetoxypenicillanic acidmethyl ester 1-oxide is dissolved in 30 ml of toluene, 445 mg (2.65mmole) of 2-mercaptobenzthiazole are added and the mixture is refluxedfor 60 minutes in a nitrogen atmosphere, The solvent is distilled off invacuo and the residue is chromatographed over silica gel. By elutingwith toluene/ethyl acetate (19:1) the title compound is obtained in theform of a faintish brown oil.

IR spectrum (in methylene chloride): characteristic bands at 3.45, 5.62,5.75, 6.27, 6.71, 6.89, 7.05, 7.30, 7.54, 7.68, 8.15, 8.55, 9.15, 9.35and 9.95μ; TLC: Rf=0.63 (toluene/ethyl acetate 1:1).

EXAMPLE 42:2[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl-3-methylcrotonicacid methyl ester

0.4 ml of triethylamine is added to a solution of 1.28 g (2.41 mmole) of2-(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl-3-methylenebutyricacid methyl ester in 30 ml of methylene chloride and the mixture isstirred at room temperature for 30 minutes. The reaction mixture isdiluted with 50 ml of methylene chloride, washed in succession with 2Nhydrochloric acid, water and sodium chloride solution, dried over sodiumsulphate and freed from solvent in vacuo. The residue is purified bychromatography over silica gel with toluene/ethyl acetate (19:1) andyields the title compound in the form of a faint yellow oil.

IR spectrum (in methylene chloride): characteristic absorption bands at3.46, 5.69, 5.82, 5.90, 6.28, 6.73, 6.90, 7.06, 7.28, 7.38, 7.75, 8.20,8.60, 9.27 and 9.96 μ; TLC : Rf=0.61 (toluene/ethyl acetate 1:1).

EXAMPLE 43:2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl-3-methylcrotonicacid methyl ester

A solution of 687 mg (1.29 mmole) of2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2oxoazetidin-1-yl]-3-methylcrotonicacid methyl ester in 14 ml of dimethylformamide is added to a solution,cooled to -20°, of 76 mg (2 mmole) of sodium borohydride in 10 ml ofdimethylformamide and the mixture is stirred at the same temperature for10 minutes. 7 ml of freshly distilled acetyl bromide are added to thereaction mixture, which is further stirred at 0° for 40 minutes. Afteradding 400 ml of benzene, the reaction mixture is washed in successionwith aqueous sodium bicarbonate solution, water and sodium chloridesolution, dried over sodium sulphate and concentrated by evaporation invacuo. After chromatography over silica gel with toluene/ethyl acetate(19:1) the residue yields the title compound in the form of an oil,which is further purified on silica gel plates with toluene/ethylacetate (4:1). The title compound is obtained in oily form.

IR spectrum (in methylene chloride): characteristic absorption bands at3.45, 5.63, 5.83, 6.27, 6.70, 7.00, 7.25, 7.35, 8.15, 8.58, 8.93 and9.20 μ; TLC: R_(f) =0.54 (toluene/ethyl acetate 1:1).

EXAMPLE 44:2[-(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-oxoaceticacid methyl ester

4 equivalents of ozone are conveyed through a solution, cooled to -20°,of 170 mg (0.42 mmole) of2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin1-yl]-3-methylcrotonicacid methyl ester in 5 ml of ethyl acetate. The reaction mixture isdiluted with 5 ml of ethyl acetate, and shaken vigorously with a 10%aqueous sodium bisulphite solution. The organic phase is separated off,washed with water and saturated sodium chloride solution, dried oversodium sulphate and concentrated by evaporation in vacuo.

IR spectrum of the resulting oily title compound (in methylenechloride): characteristic bands at 3.38, 5.48, 5.63, 5.70, 5.83, 6.27,6.70, 7.00, 7.40, 8.07, 8.25, 8.63 and 8.95 μ. The resulting product canbe used in the next step without further purification.

EXAMPLE 45: (3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidine

A solution of 129 mg (0.34 mmole) of(3S,4R)-2-(4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl)-2-oxoaceticacid methyl ester (crude product) in 10 ml of 1% aqueous methanol isstirred for 4 hours at room temperature. The reaction mixture is dilutedwith 50 ml of methylene chloride, washed in succession with water andsaturated sodium chloride solution, dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is chromatographedover silica gel with toluene/ethyl acetate (9:1) and yields the titlecompound.

IR spectrum (in methylene chloride): characteristic bands at 2.95, 3.45,5.55, 5.60, 5.88, 6.25, 6.68, 8.33 and 8.85 82 ; TLC: R_(f) =0.36(toluene/ethyl acetate 1:1).

EXAMPLE 46:2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1yl]-2-hydroxyaceticacid p-nitrobenzyl ester

760 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 4 g ofmolecular sieve A4 are added to a solution of 283 mg of(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 8 ml oftoluene and 2 ml of dimethylformamide, and the mixture is stirredovernight at room temperature. The molecular sieves are filtered offfrom the mixture and the filtrate is concentrated by evaporation invacuo. The residue is chromatographed over silica gel, and the titlecompound, contaminated with some glyoxylate, is obtained by eluting withtoluene/ethyl acetate (9:1 and 4:1).

EXAMPLE 47: 2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acidp-nitrobenzyl ester

(a) A suspension of 2 g of poly-Hunig base in 8 ml of dioxan is stirredat room temperature for 30 minutes, a solution of 962 mg of 2-(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl-2-hydroxyaceticacid p-nitrobenzyl ester in 10 ml of dioxan is added, then a solution of0.38 ml of thionyl chloride in 8 ml of dioxan is added slowly. Themixture is stirred for 2 hours at room temperature, the poly-Hunig baseis filtered off and the filtrate is concentrated by evaporation invacuo. The residue is purified by chromatography over silica gel withtoluene/ethyl acetate (1:1) and yields the2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester in crude form.

(b) 786 mg of triphenylphosphine and 3 g of poly-Hunig base are added toa solution of 960 mg of2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester in 40 ml of dioxan and the mixture is stirredovernight at 50° under nitrogen. The poly-Hunig base is removed byfiltration and the filtrate is concentrated by evaporation in vacuo. Theresidue is chromatographed over silica gel with toluene/ethyl acetate(9:1, 4:1 and 1:1) and yields the title compound. IR spectrum (inmethylene chloride): characteristic absorption bands at 5.7, 5.9, 6.17,6.55 and 7.45 μ.

EXAMPLE 48: (5R,6S)-2-methyl-6-phenoxyacetoxy-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of hydroquinone is added to a solution of 285 mg of2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 100 ml of absolute toluene and the mixtureis stirred under nitrogen for 35 hours at 90° . The toluene isevaporated off in vacuo and the residue is chromatographed over silicagel with toluene/ethyl acetate (19:1). The title compound is obtained inthe form of an oil.

IR spectrum (in methylene chloride): characteristic absorption bands at5.55, 6.30, 6.55 and 7.42 μ.

EXAMPLE 49: (5R,6S)-2-methyl-6-phenoxvacetoxy-2-penem-3-carboxylic acid

75 mg of 10 % palladium/carbon catalyst are added to a solution of 45 mgof (5R,6S)-2-methyl-6-phenoxyacetoxy-2-penem-3-carboxylic acidp-nitrobenzyl ester in a mixture of 2 ml of ethyl acetate and 2 ml of 2Msodium bicarbonate solution, and the mixture is hydrogenated underatmospheric pressure for 1.5 hours at room temperature. The hydrogenatedmixture is filtered through diatomaceous earth and the filter residue iswashed with 1 ml of 2M aqueous sodium bicarbonate solution and methylacetate. The aqueous phase is separated off from the filtrate, acidifiedwith 0.1M aqueous citric acid and extracted several times with methylenechloride. The combined methylene chloride extracts are dried over sodiumsulphate and concentrated by evaporation in vacuo.

IR spectrum (in ethanol) of the resulting crude title compound:characteristic absorption bands at 5.6 μ; UV spectrum (in ethanol):λ_(max) =305 nm.

EXAMPLE 50: 6α-methoxypencillanic acid 2,2,2-trichloroethyl ester1-oxide

A solution of 2 g of 6α-methoxypenicillanic acid 2,2,2-trichloroethylester (produced according to P. J. Giddins, D. I. Johns, E. J. Thomas:T. L. 11, 995, 1978) in 100 ml of methylene chloride and 0.3 ml ofacetone is cooled to -15° C., 1 ml of 40% peracetic acid is added overthe course of 5 minutes, and the mixture is stirred for 15 minutes atthe same temperature. Subsequently 15 ml of a 0.1N sodium thiosulphatesolution are added to the reaction mixture. The organic solution isseparated off and washed twice with ice water. After drying over sodiumsulphate the solvent is evaporated off in vacuo and the residue isrecrystallised from ether/petroleum ether. The resulting compound hasthe following physico-chemical properties: Mp.=127°-128°. IR spectrum(in methylene chloride): characteristic absorption bands at 3.41, 5.58,5.65, 8.33, 8.47, 8.70 and 9.48 μ.

EXAMPLE 51:2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylenebutyricacid 2,2,2-trichloroethyl ester

1.39 g of 2-mercaptobenzthiazol are added to a solution of 3 g of6α-methoxypenicillanic acid 2,2,2-trichloroethyl ester 1-oxide in 40 mlof absolute toluene, and the mixture is refluxed for 105 minutes undernitrogen. The solvent is distilled off in vacuo and yields the titlecompound in the form of a yellowish oil.

IR spectrum (in methylene chloride): characteristic absorption bands at3.39, 5.60, 5.65, 6.85, 8.20, 8.62, 8.97, 9.85 and 9.95 μ.

The resulting product can be used in the next step without furtherpurification.

EXAMPLE 52:2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonicacid 2,2,2-trichloroethyl ester

0.78 ml of triethylamine is added to a solution of 4.17 g of 2-(3S,4R)-4-benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl-3-methylenebutyricacid 2,2,2-trichloroethyl ester in 75 ml of absolute methylene chlorideat 0° and the mixture is stirred at this temperature for 15 minutes.

The reaction mixture is washed in succession with 4N phosphoric acid,saturated aqueous sodium bicarbonate solution and sodium chloridesolution, and dried over sodium sulphate. The solvent is evaporated offand the residue is purified by chromatography over silica gel withtoluene and toluene/ethyl acetate (19:1). The title compound is obtainedin the form of an oil. IR spectrum (in methylene chloride):characteristic absorption bands at 3.39, 5.62, 5.76, 6.85, 7.04, 7.25,6.85, 9.01, 9.48, 9.85 and 9.95 μ.

EXAMPLE 53:2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonicacid 2,2,2-trichloroethyl ester

A solution of 3.26 g of 2-(3S,4R)-4-(benzthiazol-2-yldithio]-3-methoxy-2-oxoazetidin-1-yl]-3-methyl-crotonicacid 2,2,2-trichloroethyl ester in 36.3 ml of acetic anhydride and 12.4ml of acetic acid is cooled to -15° and 1.7 g of triphenylphosphine areadded. After stirring under nitrogen at the same temperature for 75minutes, 24.8 ml of pyridine are added to the mixture. After stirringfor a further 3 hours at 0°, the reaction mixture is concentrated byevaporation under reduced pressure and the resulting residue is purifiedby chromatography over silica gel with toluene and toluene/ethyl acetate(19:1). IR spectrum (in methylene chloride): characteristic absorptionbands at 3.40, 5.63, 5.77, 5.80, 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and11.90 μ.

EXAMPLE 54:2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acid2,2,2-trichloroethyl ester

3 equivalents of ozone are conveyed through a solution, cooled to -30°,of 8.4 g of 2-[4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid2,2,2-trichloroethyl ester in 765 ml of methyl acetate. After treatingwith ozone, the reaction mixture is left to stand at the sametemperature for 15 minutes and then the excess ozone is removed by anitrogen current. The reaction mixture is washed at 0° with a 10%aqueous sodium bisulphite solution and then with sodium chloridesolution. After separating off, the combined aqueous phases areextracted a further 4 times with methyl acetate. The combined methylester solutions are dried over sodium sulphate and concentrated byevaporation in vacuo.

IR spectrum of the resulting oily title compound (in methylenechloride): characteristic absorption bands at 3.39, 5.48, 5.63, 6.09,6.94, 7.25, 7.38, 7.46, 8.23, 8.93, 9.90 and 11.83 μ.

EXAMPLE 55: (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine

(a) A solution of 1.52 g of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acid2,2,2-trichloroethyl ester (crude product) in 290 ml of methanol, 40 mlof methyl acetate and 5.9 ml of water is refluxed for 20 minutes undernitrogen. The solvent is evaporated off in vacuo. After chromatographyover silica gel with toluene/ethyl acetate (3:1) the residue yields thetitle compound.

IR spectrum (in methylene chloride): characteristic absorption bands at2.95, 3.40, 5.60, 5.88, 7.37, 7.52, 8.25, 8.70, 8.85, 10.5 and 12.12 μ.

The same compound may also be obtained as follows:

(b) 1.5 equivalents of an aqueous sodium thioacetate solution are addedto a solution of 40 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine(for manufacture see below) in 1.5 ml of phosphate buffer of a pH of 7and 0.1 ml of dioxan, and the mixture is stirred for 30 minutes at roomtemperature. The reaction mixture is extracted with methylene chlorideand the separated organic solution is then dried over sodium sulphate.The solvent is evaporated off in vacuo and the residue is purified bychromatography over silica gel with toluene/ethyl acetate (3:1). The IRspectrum of the resulting title compound (in methylene chloride) isidentical to that of the product obtained according to a).

EXAMPLE 56:2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester

1.15 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 4 g ofmolecular sieves A4are added to a solution of 350 mg of(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 24 ml ofabsolute toluene and 6 ml of absolute dimethylformamide and the mixtureis stirred overnight at room temperature under nitrogen. The molecularsieves are filtered off and the filtrate is concentrated by evaporationin vacuo. The residue is chromatographed over silica gel, and the titlecompound is obtained by eluting with toluene and toluene/ethyl acetate(19:1).

IR spectrum (in methylene chloride): characteristic absorption bands at2.86, 3.39, 5.60, 5.68, 5.88, 6.21, 6.56, 7.41, 8.26, 9.01 and 11.76 μ.

EXAMPLE 57:2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester

A solution of 0.6 g of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester in 7 ml of dry tetrahydrofuran is cooled to-15° and 0.19 ml of thionyl chloride is added.

0.37 ml of triethylamine in 0.4 ml of dry tetrahydrofuran is then addeddropwise at the same temperature. The reaction mixture is stirred for 1hour at 0°, diluted with cold methylene chloride and washed with anice-cold 2N HCl solution. After extracting several times by shaking withwater, the methylene chloride solution is dried over sodium sulphate andconcentrated by evaporation.

IR spectrum (in methylene chloride): characteristic absorption bands at3.41, 5.59, 5.65, 5.88, 6.21, 6.56, 7.41, 8.23, 8.55, 9.05, 10.5 and11.76 μ.

EXAMPLE 58:2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-]2-trichenylphosphoranylideneaceticacid p-nitrobenzyl ester

0.84 g of triphenylphosphine is added to a solution of 0.63 g of2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-chloroacetic acidp-nitrobenzyl ester in 1.8 ml of dry tetrahydrofuran, and the mixture isstirred overnight at room temperature under nitrogen. The mixture isdiluted with methylene chloride and washed with a cold, saturated,aqueous sodium bicarbonate solution. Additional washing with water,drying over sodium sulphate and concentrating by evaporation in vacuoyield the crude title compound which is purified by chromatography oversilica gel with toluene/ethyl acetate (19:1 to 3:1).

IR spectrum (in methylene chloride): characteristic absorption bands at3.40, 5.67, 5.90, 6.20, 6.58, 7.46 and 9.05 μ.

EXAMPLE 59: (5R,6S)-2-methyl-6-methoxy-2-penem-3-carboxylic acidp-nitrobenzyl ester

A catalytic amount of 3,5-di-tert.butyl-4-hydroxytoluene is added to asolution of 74 mg of2-(3S-,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-tri-phenylphosphoranylideneaceticacid p-nitrobenzyl ester in 30 ml of absolute toluene and the mixture isrefluxed under nitrogen for 3 hours. The toluene is evaporated off invacuo and the residue is chromatographed over silica gel withtoluene/ethyl acetate (19:1). The title compound is obtained in thesolid state.

IR spectrum (in methylene chloride): characteristic absorption bands at3.41, 5.60, 5.85, 6.63, 6.58, 7.41, 7.60, 8.23, 9.26 and 11.76 μ.

EXAMPLE 60:3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)-2-oxoazetidine(racemic cis-trans compound)

(a) A solution of 0.78 g (5 mmole) of 4-acetoxy-3-ethyl-azetidin-2-one(racemic mixture of cis- and trans-isomer in a ratio of 6:4) in 2 ml ofdioxan is added dropwise under a nitrogen atmosphere to a solution of1.175 g of potassium (2-acetylaminoethyl)trithiocarbonate in 20 ml ofpre-cooled phosphate buffer of a pH of 7 and the mixture is stirred for60 minutes. The reaction mixture is centrifuged, the supernatant clearsolution is decanted off and the oily residue is taken up in methylenechloride. The organic phase is dried over sodium sulphate andconcentrated by evaporation in vacuo. The residue is triturated oncewith diethyl ether and is further processed in this form.

TLC: R_(f) =0.16 (ethyl acetate); IR spectrum (CH₂ Cl₂): absorptionbands at 2.92, 2.97, 5.63, 5.97, 6.62, 9.35 and 12.34 μ.

The two starting materials may be produced as follows:

(b) 42.7 g (26.3 ml, 0.302 mole) of N-chlorosulphonyl isocyanate areadded dropwise at -10° over the course of 30 minutes to a stirredsolution of 34.5 g (0.302 mole) of but-1-enyl acetate in 35 ml of drymethylene chloride. After a further 4 hours of stirring at 0°, thereaction mixture is diluted with 50 ml of pre-cooled methylene chlorideand added dropwise to a hydrolysing mixture of 32 ml of water, 144 g ofice, 113 g of sodium bicarbonate and 38.2 g of anhydrous sodiumsulphite. During the hydrolysis the temperature is maintained at 0° byexternal cooling. When the organic phase no longer has an acidicreaction, the reaction mixture is diluted with 100 ml of diethyl etherand filtered through celite. The organic phase is separated off, theaqueous phase is extracted three times with 400 ml of diethyl ether, theorganic phases are combined, dried and concentrated by evaporation invacuo. The residue is chromatographed over silica gel with toluene/ethylacetate (2:1) and yields a racemic mixture of cis- andtrans-4-acetoxy-3-ethylazetidin-2-one in a ratio of 6:4 in oily form. IRspectrum (CH₂ Cl₂): absorption bands at 2.94, 5.60, 5.75, 7.35, 8.06 and8.85 μ.

(c) A solution of 1.708 g (14.35 mmole) of 2-acetylaminoethyl mercaptanin 2 ml of absolute ethanol is added dropwise over the course of 0.5hours, while stirring and cooling to 10°-15°, to a solution of 0.80 g(14.35 mmole) of potassium hydroxide in 5 ml of absolute ethanol. Aftera further half hour, a solution of 1.09 g (14.35 mmole) of carbondisulphide in 3 ml of absolute ethanol is added, the temperature beingmaintained at 10°-15°. The reaction mixture is further stirred for 3hours at room temperature and cooled in an ice bath for 20 minutes. Theyellow crystalline precipitate is filtered off, washed once withabsolute ethanol and yields potassium(2-acetylaminoethyl)-trithiocarbonate having a melting point of171°-174°.

IR spectrum (KBr): absorption bands at 2.95, 6.18,6.50, 7.00, 7.32,7.43, 7.79, 8.33, 9.09 and 11.83 μ.

EXAMPLE 61:2-[3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester (racemic cis-trans compound)

4.20 g (16.5 mmole) of 2-ethoxy-2-hydroxyacetic acid δ-nitrobenzyl esterare added at room temperature to a solution of 3.30 g (11 mmole) of3-ethyl-4-(2-acetylaninoethylthiothiocarbonylthio-2-oxoazetidine(racemic cis-trans compound) in 120 ml of toluene and 32 ml ofdimethylformamide. After adding freshly dried molecular sieves themixture is stirred under nitrogen for 3 hours at room temperature. Themolecular sieves are filtered off, washed with 20 ml of toluene and thefiltrate and washing liquid are together concentrated by evaporation invacuo. The residue is dried in a high vacuum and then triturated withdiethyl ether to remove unreacted 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester. The title compound with the followingphysico-chemical properties is obtained:

TLC: R_(f) =0.16 (ethyl acetate); IR spectrum (CH₂ C1₂): absorptionbands at 2.86, 2.92, 3.03, 5.65, 5.71, 5.97, 6.58, 7.41 and 8.37 μ.

EXAMPLE 62:2-3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)-2-oxoazetidin-1-yl-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic cis-trans compound)

A solution of 5.52 g (11 mole) of 2 -[3-ethyl-4-(2-acetylaminoethylthiothiocarbon-ylthio)-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester (racemic cis-trans compound) in 30 ml ofabsolute tetrahydrofuran is cooled to -15°, while stirring 1.02 ml (14mmole) of thionyl chloride are added and subsequently 1.95 ml (14 mmole)of triethylamine are slowly added. The reaction mixture is stirred for20 minutes at 0°, 150 ml of methylene chloride are added and washing iscarried out with ice-cold 1N hydrochloric acid. The organic phase isdried with sodium sulphate and concentrated by evaporation in vacuo. Theresulting crude2-3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)-2-oxoazetidin-1-yl-2-chloroaceticacid p-nitrobenzyl ester is dissolved in 3 ml of dry tetrahydrofuran, 6g of triphenylphosphine are added and the mixture is stirred for 24hours at room temperature. The reaction mixture is diluted with 200 mlof methylene chloride, washed with saturated aqueous sodium bicarbonatesolution, dried over sodium sulphate and concentrated by evaporation invacuo. After chromatography over silica gel with ethyl acetate, theresidue yields the title compound.

TLC: R_(f) =0.19 (ethyl acetate); IR spectrum (CH₂ Cl₂): absorptionbands at 2.93, 5.70, 5.97, 6.17, 6.58, 6.99, 7.00, 8.07, 8.33 and 9.39μ.

EXAMPLE 63: 2-(2-acetylaminoethylthio)-6-ethyl-2-penem-3-carboxylic acidp-nitrobenzyl ester (racemic cis- and trans-compound)

A catalytic amount of hydroquinone is added to a solution of 1.75 g(2.34 mmole) of2[-3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)-2-oxoazetidin-1-yl]-2-tri-phenyl-phos-phoranylideneaceticacid p-nitrobenzyl ester (racemic cis-trans compound) in 1500 ml of dryo-xylene and the mixture is refluxed for 7 hours while stirring undernitrogen. The solvent is evaporated off in vacuo and the residue ischromatographed over silica gel with ethyl acetate. A mixture of thecis- and trans-title compound is obtained.

The cis- and the trans-title compound may be obtained by a combinationof preparative thin layer chromatography (silica gel with methylisobutyl ketone) and column chromatography (silica gel with ethylacetate).

cis-compound: Melting point 141°-142° (after crystallisation frommethylene chloride/diethyl ether); TLC: R_(f) 0.62 (methyl isobutylketone); IR spectrum (CH₂ Cl₂): absorption bands at 2.93, 5.62, 5.98,6.60, 7.46, 7.57, 8.44 and 9.09 μ.

trans-compound: Melting point 132°-133° (after crystallisation frommethylene chloride/diethyl ether); TLC: R_(f) =0.56 (methyl isobutylketone); IR spectrum (CH₂ Cl₂): absorption bands at 2.92, 5.62, 5.96,6.58, 7.44, 7.58, 8.40 and 9.01 μ.

EXAMPLE 64: 2-(2-acetylaminoethylthio)-6-ethyl-2-penem-3-carboxylic acid(racemic cis- and trans-compound)

(a) 4 ml of 0.2N aqueous sodium bicarbonate solution and 200 mg of 10%palladium/carbon catalyst are added to a solution of 100 mg (0.22 mmole)of 2-(2 acetylaminoethylthio)-6-ethyl-2-penem-3-carboxylic acidp-nitrobenzyl ester (racemic cis-compound in 6 ml of absolute ethylacetate and the mixture is stirred at normal pressure for 60 minutesunder hydrogen. The catalyst is filtered off from the hydrogenatedmixture over diatomaceous earth. The aqueous phase is separated off,washed with diethyl ether, acidified with 5% aqueous citric acidsolution and exhaustively extracted with methylene chloride. Thecombined methylene chloride phases are dried over sodium sulphate,filtered, concentrated by evaporation in vacuo and dried in a highvacuum. The resulting cis-title compound has the followingphysico-chemical properties: melting point 153-154° (methylenechloride/diethyl ether; IR spectrum (KBr): absorption bands at 3.08,3.22, 3.39, 3.42, 3.50, 3.77, 4.08, 5.67, 6.06, 6.21, 6.35, 6.75, 7.04,7.69, 7.93, 8.27, 9.01, 9.62 and 14.38 μ.

b) In the safe manner the trans-title compound is obtained from 100 mgof 2-(2-acetylaminoethylthio)-ethyl-2-penem-3-carboxylic acidp-nitrobenzyl ester (racemic trans-compound).

IR spectrum (KBr): absorption bands at 3.01, 3.39, 3.44, 5.68, 6.10,6.85, 7.75, 8.16, 8.47 and 8.93 μ.

EXAMPLE 65:3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidine(racemic cis-trans compound in a ratio of 1:4)

A solution, prepared in the cold, of 7.95 g (26.7 mmole) of4-p-nitrobenzyloxycarbonylaminothiobutyric acid in 26.7 ml of 1N sodiumhydroxide solution is added dropwise to a pre-cooled solution of 3.24 g(20 mmole) of 3-ethyl-4-acetoxyazetidin-2-one (racemic cis-transcompound in a ratio of 6:4) in 50 ml of dioxan and the mixture isstirred for 2 hours at room temperature. The reaction mixture isexhaustively extracted with methylene chloride. The combined organicphases are dried over sodium sulphate and concentrated by evaporation invacuo. The residue is chromatographed over silica gel with toluene/ethylacetate (9:1, 4:1 and 1:1) and yields the title compound with thefollowing physico-chemical properties.

TLC: R_(f) =0.10 (toluene/ethyl acetate 1:1);

IR spectrum (CH₂ Cl₂): absorption bands at 2.81, 2.92, 5.66, 5.81, 5.94,6.58, 7.52 and 8.20 μ.

The thiocarboxylic acid used as starting material is obtained asfollows:

(a) A solution of 25.87 g (0.12 mmole) of p-nitrobenzyl chloroformate in100 ml of dry dioxan is added dropwise over the course of 20 minutes toa solution of 10.30 g (0.1 mmole) of 4-aminobutyric acid in 300 ml of 1Nsodium hydroxide solution in an ice bath. The reaction mixture isstirred at room temperature for 3 hours, washed with ethyl acetate andacidified with 2N hydrochloric acid. The precipitated4-p-nitrobenzyloxycarbonylaminobutyric acid is filtered off andrecrystallised from ethyl acetate; melting point 145-146°.

(b) In succession, 2.2 g (20 mmole) of triethylamine and a solution of1.4 ml (10 mmole) of isobutyl chloroformate in 20 ml of dry methylenechloride are added dropwise to a solution, cooled to -10°, of 2.82 g (10mmole) of 4-p-nitrobenzyloxycarbonylaminobutyric acid in 50 ml of drymethylene chloride. The reaction mixture is stirred for one hour andthen a strong current of hydrogen sulphide is conveyed through for 2hours. After acidifying with 2N sulphuric acid, the organic phase isseparated off, dried and concentrated by evaporation in vacuo. Theresulting 4-p-nitrobenzyloxycarbonylaminothiobutyric acid can be furtherprocessed without further purification.

EXAMPLE 66:2-[3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester (racemic cis-trans compound)

At room temperature 6.50 g (16.45 mmole) of3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidine(racemic cis-trans compound) and 8.41 g of 2-ethoxy-2-hydroxyacetic acidp-nitrobenzyl ester are dissolved in 160 ml of toluene and 40 ml ofdimethylformamide. After adding approximately 15 g of freshly driedmolecular sieves, the mixture is stirred at room temperature for 3 hoursunder nitrogen. The molecular sieves are filtered off and washed withdimethylfornanide/toluene (1:4). The filtrate is concentrated byevaporation in vacuo, dried in a high vacuum and the residue istriturated with diethyl ether to remove unreacted2-ethoxy-2-hydroxyacetic acid -p-nitrobenzyl ester. The crude titlecompound has the following physico-chemical properties:

TLC: R_(f) =0.1 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.83, 2.90, 5.67, 5.73, 5.80, 5.99, 6.58, 7.52, 8.26and 9.52 μ.

EXAMPLE 67:2-[3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester (racemic cis-trans compound)

(a) 3.06 ml (42 mmole) of thionyl chloride and 5.85 ml (42 mmole) oftriethylamine are added dropwise, in succession, at -15° to a mixture of10.40 g (17.2 mmole) of2-3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester in 40 ml of absolute dioxan. The reactionmixture is stirred for 20 minutes at 0° under nitrogen, diluted with 200ml of methylene chloride and washed with cooled 1N hydrochloric acid.The organic phase is dried and concentrated by evaporation in vacuo.

(b) The resulting crude2-[3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester is dissolved in a minimumamount of tetrahydrofuran, 9 g of triphenylphosphine are added and themixture is stirred overnight at room temperature under nitrogen. Thereaction mixture is diluted with 250 ml of methylene chloride, washedwith saturated aqueous sodium bicarbonate solution, dried andconcentrated by evaporation in vacuo. The residue is chromatographedover silica gel with toluene/ethyl acetate (1:1) and yields the titlecompound with the following physico-chemical properties:

TLC: R_(f) =0.05 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.90, 5.73, 5.80, 5.94, 6.58, 7.52, 8.20 and 9.35 μ.

EXAMPLE 68:6-ethyl-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-2-penem-3-carboxylicacid p-nitrobenzyl ester (racemic cis-trans compound)

A catalytic amount of hydroquinone is added to a solution of 5.40 g(6.36 mmole) of2[-3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazetidin-1-yl-2-triph-enylph-os-phoranylideneaceticacid -p-nitrobenzyl ester (racemic cis-trans compound) in 1500 ml of drytoluene and the mixture is stirred under nitrogen for 20 hours at 100°.The solvent is evaporated off in vacuo and the residue ischromatographed over silica gel with toluene/ethyl acetate (4:1). Amixture of the cis- and trans-title compound is obtained in the ratio of1:10 with the following physico-chemical properties:

TLC R_(f) =0.22 (toluene/ethyl acetate 1:1); IR spectrum (CH₂ Cl₂):absorption bands at 2.90, 5.62, 5.81, 5.85, 6.58, 7.52, 7.87 and 8.20 μ.By repeated chromatography the cis- and the trans-compound can beobtained in pure form.

EXAMPLE 69: 6-ethyl-2-(3-aminopropyl)-2-penem-3-carboxylic acid (racemiccis-trans compound)

2 g of disodium biphosphate and 4 g of 10% palladium/carbon catalyst areadded to a solution of 2 g (3.5 mmole) of6-ethyl-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-2-penem-3-carboxylicacid p-nitrobenzyl ester (racemic cis-trans compound) in 600 ml ofdioxan, 330 ml of ethanol and 600 ml of water, and the mixture isstirred at normal pressure for one hour under hydrogen. The catalyst isfiltered off from the hydrogenated mixture over diatomaceous earth. Thefiltrate is washed 3 times with 1500 ml of ethyl acetate andlyophilised. The lyophilisate is chromatographed twice over silylatedsilica gel (thin layer plates ANTEC-GEL, UP-C₁₂) with water/acetonitrile(9:1) and yields the title compound (cis:trans approximately 1:10) withthe following physico-chemical properties: TLC (ANTEC-GEL, UP-C₁₂) R_(f)=0.55 (water/acetonitrile 9:1); IR spectrum (KBr): absorption bands at2.94, 3.39, 5.68, 6.41, 7.33, 7.81, 8.93, 12.82 and 14.28 μ.

Using the pure cis- or trans-starting material, the pure cis- andtrans-title compounds can be obtained.

EXAMPLE 70: 2-[(3S,4S)- and(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl-3-methylenebutyric acidβ, β, β-trichloroethyl ester

0.114 ml of glacial acetic acid and 0.35 ml of trimethyl phosphite areadded to 200 mg of (6S)-6-methoxypenicillanic acid β,β,β-trichloroethylester 1-oxide in 13 ml of absolute benzene and the mixture is refluxedfor 7 hours. The solvent is evaporated off in vacuo and the residue ispurified by chromatography over silica gel with toluene/ethyl acetate(19:1 and 9:1).

The title compounds can thus be separated. IR spectrum (in methylenechloride): characteristic absorption bands for (3S,4R)isomer(trans-compound) 3.42, 5.62, 5.68, 7.25, 7.35, 8.26, 9.01, 10.93 and11.83μ; (3S,4S)-isomer (cis-compound): 3.42, 5.61, 5.7, 7.25, 7.35,8.21, 9.61 and 10.93μ.

The ratio of cis to trans-compound is approximately 1:1.

EXAMPLE 71 2-[(3S,4S)- and(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl]-2-methylcrotonic acidβ,β,β-trichloroethyl ester.

A solution of 0.93 g of 2- [(3S,4S)- and(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl]-3-methylenebutyric acidβ,β,β-trichloroethyl ester in 60 ml of absolute methylene chloride iscooled to 0° and stirred for 10 minutes with 0.33 ml of triethylamine.The reaction mixture is then washed in succession with 4N phosphoricacid, saturated aqueous sodium bicarbonate solution and water and driedover sodium sulphate. The solvent is evaporated off in vacuo and theresidue is purified by chromatography over silica gel.

IR spectrum (in methylene chloride): characteristic absorption bands at:3.41, 5.60, 5.73, 6.13, 7.19, 7.33, 8.26, 9.09, 9.57, 10.64, 10.87 and12.19μ.

EXAMPLE 72 2-[(3S,4S)- and(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acidβ,β,β-trichloroethyl ester

3 equivalents of ozone are conveyed through a solution, cooled to -30°,of 0.91 g of 2-[(3S,4S)- and(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl-3-methylcrotonic acidβ,β,β-trichloroethyl ester in 130 ml of methyl acetate. After the ozonetreatment, the mixture is left to stand for 15 minutes at the sametemperature and subsequently the excess ozone is removed by a nitrogencurrent. The reaction mixture is washed at 0° with a 10% aqueous sodiumsulphite solution and then with sodium chloride solution. The combinedaqueous solutions are reextracted a further three times with methylacetate. The combined organic extracts are dried over sodium sulphateand concentrated by evaporation in vacuo.

IR spectrum (in methylene chloride): characteristic absorption bands at3.41, 5.46, 5.68, 5.81, 7.27, 7.43, 8.23, 8.40, 9.52 and 9.90μ.

EXAMPLE 73 (3S,4S)- and (3S,4R)-4-acetoxy-3-methoxy -2-oxoazetidine

A solution of 120 mg of 2- [(3S,4S)- and(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl-2-oxoacetic acidβ,β,β-trichloroethyl ester in 25 ml of methanol, 3.5 ml of methylacetate and 0.5 ml of water is refluxed for 20 minutes. The solvent isevaporated off in vacuo and the residue yields, after chromatographyover silica gel with toluene/ethyl acetate (9:1) the pure(3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidine;

IR spectrum (in methylene chloride): characteristic absorption bands at2.96, 3.42, 5.57, 5.73, 7.30, 8.23, 8.70, 8.85, 9.62, 10.0 and 10.20μ,and on further elution the pure (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine; IR spectrum (in methylene chloride): characteristicabsorption bands at 2.94, 3.41, 5.56, 5.73, 7.35, 7.49, 8.20 and 9.52μ.

EXAMPLE 74(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidine

A solution of 422 mg of potassium 2-p-nitrobenzyloxycarbonylaminoethyltrithiocarbonate in 1 ml of water is added dropwise at room temperatureunder, a nitrogen atmosphere to a solution of 159 mg (1 mmole) of(3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 3 ml of phosphate bufferof a pH of 7 and 0.2 ml of dioxan, and the mixture is stirred at thesame temperature for 30 minutes. The reaction mixture is exhaustivelyextracted with methylene chloride. The combined organic phases are driedover sodium sulphate and concentrated by evaporation in vacuo. Theresidue is chromatographed over silica gel and yields the title compoundwith the following

IR spectrum (in methylene chloride): characteristic absorption bands at2.95, 5.62, 5.78, 6.21, 6.56, 7.41, 8.26 and 9.25μ.

EXAMPLE 75 2-[(3S,4R)-4-(2-pnitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester

Analogously to Example 23, 646 mg (1.5 mmole) of(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidinein 22 ml of absolute toluene and 5.5 ml of absolute dimethylformamideare reacted with 848 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzylester in the presence of freshly dried molecular sieves. After workingup and chromatography over silica gel the title compound is obtained.

IR spectrum (in methylene chloride): characteristic absorption bands at5.62, 5.7, 5.78, 6.56, 7.41 and 8.26μ.

EXAMPLE 762-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

Analogously to Example 24, 0.12 ml of thionyl chloride and 0.23 ml oftriethylamine in 0.23 ml of absolute tetrahydrofuran are added to asolution of 640 mg of2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester in 4.5 ml of absolute tetrahydrofuran. Afterreacting and working up, 0.54 g of triphenylphosphine is added to thecrude2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaninoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester, obtained as intermediate, in 1.15 ml ofabsolute tetrahydrofuran. After working up and chromatography oversilica gel, the title compound is obtained.

IR spectrum (in methylene chloride): characteristic absorption bands at3.4, 5.7, 5.78, 6.15, 6.55, 7.45 and 8.26μ.

EXAMPLE 77(6S,5R)-2-(2-p-nitrobenzyloxycarbonylaminoethylthio)-6-methoxy-2-penem-3-carboxylicacid p-nitrobenzyl ester

Analogously to Example 25, a solution of 500 mg of2-[(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 165 ml of absolute o-xylene is stirred underreflux.

After working up and chromatography over silica gel with toluene/ethylacetate (19:1 to 9:1) the title compound is obtained.

IR spectrum (CH₂ Cl₂): absorption bands at 5.57, 5.78, 5.9, 6.55, 7.45and 8.26μ.

EXAMPLE 78 (6S,5R)-2-(2-aminoethylthio)-6-methoxy-2-penem-3-carboxylicacid

Analogously to Example 69, a solution of 295 mg of(6S,5R)-2-(2-p-nitrobenzyloxycarbonylaminoethylthio)-6-methoxy-2-penem-3-carboxylicacid p-nitrobenzyl ester in 85 ml of dioxan, 47 ml of ethanol and 85 mlof water is treated with 286 mg of disodium hydrogen phosphate and 570mg of a 10% palladium-on-carbon catalyst, and the mixture is stirred ina hydrogen atmosphere under normal pressure. After reacting and workingup, the title compound with the following IR spectrum (KBr) is obtained:Absorption bands at 2.8-4.16, 5.68, 6.41 and 8.26μ.

EXAMPLE 79(3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidine

Analogously to Example 55b), an aqueous solution of 480 mg of4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt is added to159 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 6 ml of aphosphate buffer of a pH of 7 and 0.4 ml of dioxan After working up andchromatography over silica gel, the title compound with the following IRspectrum (CH₂ Cl₂) is obtained: characteristic absorption bands at 2.95,5.6, 5.78, 5.87, 6.56, 7.41 and 8.26μ.

EXAMPLE 80 2-[(3S,4R)-4-(4p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester

Analogously to Example 23, 400 mg of(3S,4R)-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidinein 15 ml of absolute toluene and 3.7 ml of absolute dimethylformamideare reacted with 565 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzylester in the presence of freshly dried molecular sieves. After workingup and chromatography over silica gel, the title compound with thefollowing IR spectrum (CH₂ Cl₂) is obtained: characteristic absorptionbands at 5.6, 5.7, 5.78, 5.87, 6.56, 7.41 and 8.26μ.

EXAMPLE 812-[(3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester

Analogously to Example 24, 0.12 ml of thionyl chloride and then 0.23 mlof triethylamine in 0.23 ml of absolute tetrahydrofuran are added to asolution of 606 mg of2-[(3S,4R)-4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyaceticacid p-nitrobenzyl ester in 4.5 ml of absolute tetrahydrofuran. Afterreacting and working up, 0.54 g of triphenylphosphine is added to theresulting crude2-[(3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1-yl]-2-chloroaceticacid p-nitrobenzyl ester in 1.15 ml of absolute tetrahydrofuran. Workingup and chromatography over silica gel produce the title compound withthe following IR spectrum (CH₂ Cl₂): characteristic absorption bands at5.7, 5.78, 5.9, 6.15, 6.55, 7.45 and 8.26μ.

EXAMPLE 82(6S,5R)-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-6-methoxy-2-penem-3-carboxylicacid p-nitrobenzyl ester

Analogously to Example 68, a solution of 400 mg of 2-[(3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio-3-methoxy-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneaceticacid p-nitrobenzyl ester in 160 ml of absolute toluene is stirred underreflux. After working up and chromatography over silica gel withtoluene/ethyl acetate (19:1 to 9:1) the title compound is obtained.

IR spectrum (CH₂ Cl₂): characteristic absorption bands at 5.57, 5.78,5.85, 6.55, 7.45 and 8.26μ.

EXAMPLE 83 (6S,5R)-2-(3-aminopropyl-6-methoxy-2-penem-3-carboxylic acid.

Analogously to Example 69, a solution of 572 ml of(6S,5R)-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-6-methoxy-2-penem-3-carboxylicacid p-nitrobenzyl ester in 170 m of dioxan, 94 ml of ethanol and 170 mlof water is treated with 571 mg of disodium hydrogen phosphate and 1.14g of a 10% palladium-on-carbon catalyst and is stirred in a hydrogenatmosphere under normal pressure.

After reacting and working up, the title compound with the following IRspectrum (KBr) is obtained: Absorption bands at 2.75-4.15, 5.67, 6.42and 8.25μ.

EXAMPLE 84 2-[(3S,4S)- and(3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acidβ,β,β-trichloroethyl ester

3.25 ml of a 1.1M chlorine solution in CCl₄ are added dropwise at -80°to 612 mg of (6S)-6-methoxypenicillanic acid β,β,β-trichloroethyl esterin 9 ml of absolute methylene chloride.

After stirring for 2 hours at -80°, the reaction mixture is warmed up toroom temperature in the course of one hour. The solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel 10 %water. The title compounds have the following IR spectrum (in CH₂ Cl₂):characteristic absorption bands at 3.41, 5.60, 5.76, 6.15, 7.22, 7.35,8.33, 9.09, 9.52 and 12.20μ. In the resulting mixture the ratio of(3S,4S)-compound to (3S,4R)-compound is 1:10.

EXAMPLE 85 2-[(3S,4S)- and(3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acidβ,β,β-trichloroethyl ester

3 equivalents of ozone are conveyed through a solution, cooled to -35°C., of 210 mg of 2-[(3S,4S)- and(3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acidβ,β,β-trichloroethyl ester in 30 ml of methyl acetate. After the ozonetreatment, the mixture is left to stand for 15 minutes at the sametemperature and then the excess ozone is removed by a current ofnitrogen. The reaction mixture is washed at 0° with a 10% aqueous sodiumbisulphite solution and then with sodium chloride solution. The combinedaqueous solutions are re-extracted a further 3 times with methylacetate. The organic extracts are dried over sodium sulphate andconcentrated by evaporation in vacuo. The crude title compound has thefollowing IR spectrum (in CH₂ Cl₂): characteristic absorption bands at3.41, 5.46, 5.65, 5.80, 7.46, 8.23, 8.47, 8.89, 9.57, 9.95 and 11.90μ.

EXAMPLE 86 (3S,4S)- and (3S,4R)-4-chloro-3-methoxy-2-oxoazetidine

A solution of 339 mg of 2-[(3S,4S)- and(3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acidβ,β,β-trichloroethyl ester and 197 mg of 2,4-dinitrophenylhydrazine in 9ml of tetrahydrofuran are refluxed for 30 minutes. The solvent isevaporated off and the residue is chromatographed over silica gel. Thetitle compound has the following IR spectrum (CH₂ Cl₂): Characteristicabsorption bands at 2.94, 5.56, 8.26 and 9.09μ.

EXAMPLE 87(3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidine

A solution of 350 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acidsodium salt in 4 ml of water is added dropwise to a solution of 135 mgof (3S,4R)-4-chloro-3-methoxy-2-oxoazetidine in 6 ml of a phosphatebuffer of a pH of 7 and 0.4 ml of dioxan in the presence of 150 mg ofsodium iodide.

After stirring for 30 minutes at room temperature the mixture isexhaustively extracted with methylene chloride. After removing anddrying the organic phase over sodium sulphate, the solvent is evaporatedoff in vacuo and the residue is chromatographed over silica gel. Thetitle compound has the following IR spectrum (C₂ Cl₂): Absorption bandsat 2.95, 5.6, 5.78, 5.87, 6.56, 7.41 and 8.26μ.

EXAMPLE 88

Using corresponding starting materials and by way of correspondingintermediates, the following compounds are obtained analogously to theaforegoing Examples:

6-ethyl-2-(2-aminoethylthio)-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-methyl-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-(3-aminopropyl)-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-(3-acetylaminopropyl)-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-ethylthio-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-(2-aminoethylthio)-2-penem-3-carboxylic acid,

6-hydroxymethyl-2-(2-acetylaminoethylthio-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-methyl-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-(3-aminopropyl)-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-(3-acetylaminopropyl)-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-ethylthio-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-(2-aminoethylthio)-2-penem-3-carboxylic acid,

6-(1-hydroxyethyl)-2-(2-acetylaminoethylthio)-2-penem-3-carboxylic acid,

6-methoxy-2-penem-3-carboxylic acid,

6-methoxy-2-(3-acetylaminopropyl)-2-penem-3-carboxylic acid,

6-methoxy-2-ethylthio-2-penem-3-carboxylic acid,

6-methoxy-2-(2-acetylaminoethylthio)-2-penem-3-carboxylic acid,

6-methoxy-2-(1,3,4-thiadiazol-2-ylthio)-2-penem3-carboxylic acid,

6-(2 hydroxyprop-2-yl)-2-penem-3-carboxylic acid,

6-(2-hydroxyprop-2-yl)-2-methyl-2-penem-3-carboxylic acid,

6-(2-hydroxyprop-2-yl)-2-(3-aminopropyl)-2-penem-3-carboxylic acid,

6-(2-hydroxyprop-2-yl)-2-(3-acetylaminopropyl)-2-penem-3-carboxylicacid,

6-(2-hydroxyprop-2-yl)-2-ethylthio-2-penem-3carboxylic acid,

6-(2-hydroxyprop-2-yl)-2-(2-aminoethylthio-2-penem-3-carboxylic acid,

6-(2-hydroxyprop-2-yl)-2-(2-acetylaminoethylthio-2-penem-3-carboxylicacid,

both in racemic and in optically active form, and their salts.

EXAMPLE 89

Dry ampoules or phials, containing 0.5 g of6-ethyl-2-(3-aminopropyl)-2-penem -3-carboxylic acid as activesubstance, are produced as follows: Composition (for 1 ampoule orphial):

    ______________________________________                                        Composition (for 1 ampoule or phial):                                         ______________________________________                                        active substance         0.5    g                                             mannitol                 0.05   g                                             ______________________________________                                    

A sterile aqueous solution of the active substance and the mannitol issubjected to freeze-drying under aseptic conditions in 5 ml ampoules or5 ml phials and the ampoules or phials are sealed and examined.

EXAMPLE 90

Dry ampoules or phials, containing 0.25 g of6-ethyl-2-(3-aminopropyl)-2-penem-3-carboxylic acid as active substance,are produced as follows:

    ______________________________________                                        Composition (for 1 ampoule or phial):                                         ______________________________________                                        active substance      0.25   g                                                mannitol              0.025  g                                                ______________________________________                                    

A sterile aqueous solution of the active substance and the mannitol issubjected to freeze-drying under aseptic conditions in 5 ml ampoules or5 ml phials and the ampoules or phials are sealed and examined.

What is claimed is:
 1. A compound of the formula ##STR14## wherein R_(a)is (1R)-1-hydroxyethyl;R₂ A together with the carbonyl to which it isattached is a protected carboxyl group; R₁ is -R, in which R is C₁₋₇alkyl, phenyl, phenylalkyl having 7-13 carbon atoms, or heterocyclyl orheterocyclylalkyl having up to 10 carbon atoms and up to 4 ring heteroatoms selected from nitrogen, oxygen, and sulphur, with the proviso thattwo oxygen atoms or two sulfur atoms or one oxygen atom and one sulfuratom are not adjacent to each other, each R being unsubstituted orsubstituted by amino, mono C₁₋₇ alkylamino, di-C₁₋₇ alkylamino, hydroxy,C₁₋₇ alkoxy, mercapto, C₁₋₇ alkylthio, chloro, bromo, fluoro, or bycarboxyl; and Z' is oxygen, sulfur, methoxycarbonylmethylidene or1-menthyloxycarbonylmethylidene; andthe functional groups in theradicals designated R_(a) and R₁ are either in protected or unprotectedform.
 2. A compound of the formula ##STR15## wherein R_(a) is(1R)-1-hydroxyethyl;R₂ A together with the carbonyl to which it isattached is a protected carboxyl group; R₁ is SR, in which R is C₁₋₇alkyl, phenyl, phenylalkyl having 7-13 carbon atoms, or heterocycylhaving up to 10 carbon atoms and up to 4 ring hetero atoms selected fromnitrogen, oxygen, and sulphur, with the proviso that two oxygen atoms ortwo sulfur atoms or one oxygen atom and one sulfur atom are not adjacentto each other, each R being unsubstituted or substituted by amino, monoC₁₋₇ alkylamino, di-C₁₋₇ alkylamino, hydroxy, C₁₋₇ alkoxy, mercapto,C₁₋₇ alkylthio, nitro, chloro, bromo, fluoro, cyano or carboxyl; and Z'is oxygen, sulfur, methoxycarbonylmethylidene or1-menthyloxycarbonylmethylidene; andthe functional groups in theradicals designated R_(a) and R₁ are either in protected or unprotectedform.
 3. The compound of the formula ##STR16## wherein R_(a) is(1R)-1-hydroxyethyl;R₁ is methylthio, ethylthio, aminoethylthio, 3-aminopropylthio, 4-aminobutylthio, 5-aminopentylthio, methyl, 2-furyl,2-thienyl, 2-pyridyl, or (1-methyltetrazol-5-yl)thio; and R₂ A togetherwith the carbonyl to which it is attached is a protected carboxyl group,and Z' is oxygen or sulphur.
 4. A compound of the formula ##STR17##wherein R_(a) is hydroxymethyl or (1R)-1-hydroxyethyl; R₂ A togetherwith the carbonyl to which it is attached is a protected carboxylgroup;R₁ is(a), lower alkyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, lower alkanoyloxy-lower alkyl, lower alkylthio-lower alkyl,amino-lower alkyl, lower alkanoyl-amino-lower alkyl, or carboxy-loweralkyl, (b) phenyl which is unsubstituted or substituted by lower alkyl,lower alkoxy, hydroxy, halogen, nitro, or by amino, (c) furyl, thienyl,or pyridyl, or (d) lower alkenylthio or lower alkylthio which isunsubstituted or substituted by lower alkoxy, lower alkanoyloxy, loweralkoxycarbonyl, Carbamoyl, cyano, nitro, amino, lower alkyl amino,di-lower alkyl amino, lower alkanoyl amino; or di-lower alkanoyl amino;and Z' is oxygen, sulfur, or a methoxycarbonylmethylidene or1-menthyloxycarbonylmethylidene; andthe functional groups in theradicals designated R_(a) and R₁ are either in protected or unprotectedform.
 5. The compound of claim 4 wherein R_(a) is hydroxymethyl and R₁is ethylthio.
 6. The compound of claim 4 wherein R_(a) is(1R)1-hydroxyethyl and R₁ is 3-aminopropyl.
 7. The compound of claim 4wherein R_(a) is (1R)-1-hydroxyethyl and R₁ is ethylthio.
 8. Thecompound of claim 4 wherein R_(a) is (1R)-1-hydroxyethyl and R₁isethylthio, methylthio, aminomethylthio, 3-aminopropylthio,4-aminobutylthio, methyl, 2-furyl, 2-thienyl, or 2-pyridyl.
 9. Thecompound of claim 4 wherein said R₁ amino-lower alkyl-thio is aminomethylthio or amino-C₃ -C₇ alkylthio.
 10. The compound of claim 2wherein said R₁ amino-lower alkyl-thio is amino methylthio or amino-C₃-C₇ alkylthio.
 11. The compound of claim 4 whereinR₂ A is 2-halo loweralkoxy, 2-lower alkylsulfonyl-lower alkoxy, tert.-lower alkoxy,diphenylmethoxy, 4'-dimethoxydiphenyl methoxy, lower alkenyloxy, loweralkoxyphenyl-lower alkoxy, nitrobenzyloxy, furfuryloxy, acetonyloxy,phenacryloxy, 2,4-dioxo-3-pentoxy, 1-methoxycarbonyl-2-oxopropoxy,1-ethoxycarbonyl-2oxopropoxy, 2-cyanoethoxy, 2-cyano-2-phenylethoxy,2-tri-loweralkylsilylethoxy, 2-tri-phenylsilylethoxy,2-tetrahydrofuryloxy, 2-tetrahydropyranyloxy, 2,3-dihydro-2-pyranyloxy,nitrophenoxy, polyhalophenoxy, or lower alkoxy.
 12. The compound ofclaim 2 whereinR₂ A is 2-halo lower alkoxy, 2-lower alkylsulfonyl-loweralkoxy, tert.-lower alkoxy, diphenylmethoxy, 4,4'-dimethoxyldiphenylmethoxy, lower alkenyloxy, lower alkoxyphenyl-lower alkoxy,nitrobenzyloxy, furfuryloxy, acetonyloxy, phenacyloxy,2,4-dioxo-3-pentoxy, 1-methoxycarbonyl-2-oxopropoxy,1-ethoxy-carbonyl-2-oxopropoxy, 2-cyanoethoxy, 2-cyano-2-phenylethoxy,2-tri-loweralkylsilylethoxy, 2-tri-phenylsilylethoxy,2-tetrahydrofuryloxy, 2-tetrahydropyranyloxy, 2,3-dihydro-2-pyranyloxy,nitrophenoxy, polyhalophenoxy, or lower alkoxy.